Pharmaceutical compositions of gamma-hydroxybutyrate derivatives

Abstract

A pharmaceutical composition is disclosed comprising pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid and excipient granules. When the pharmaceutical composition is mixed with water, the excipient granules rapidly dissolve to form a viscous solution having the pharmaceutical granules suspended in a viscous solution. The pharmaceutical granules provide a palatable oral pharmaceutical composition.

Description

[Technical Field]

[0001] This application claims the benefit under § 119(e) of U.S. Provisional Application No. 63 / 529,880, filed on 31 July 2023, which is incorporated in its entirety by reference.

[0002] This disclosure relates to excipient-containing granules, pharmaceutical compositions comprising excipient-containing granules, and the use of pharmaceutical compositions for preparing oral formulations of 4-((L-valyl)oxy)butanoic acid. [Background technology]

[0003] The active pharmacologically active ingredient can be administered using pharmaceutical granules. To improve the palatability of the pharmaceutical composition administered to the patient, the pharmaceutical granules can be dispersed in a viscous solution. It may be convenient to provide viscosifiers and other excipients together with the pharmaceutical granules so that the viscosifiers, other excipients, and pharmaceutical granules can be combined with water to provide an oral pharmaceutical composition. [Overview of the project]

[0004] According to the present invention, the pharmaceutical composition comprises a pharmaceutical granule containing 4-((L-valyl)oxy)butanoic acid and an excipient granule.

[0005] According to the present invention, the pharmaceutical product comprises the pharmaceutical composition according to the present invention.

[0006] According to the present invention, a unit dose comprises the pharmaceutical composition according to the present invention.

[0007] According to the present invention, a method for preparing an oral pharmaceutical composition for oral administration using a pharmaceutical composition or a pharmaceutical according to the present invention comprises combining the pharmaceutical composition with an aqueous solution and mixing the pharmaceutical composition to dissolve immediate-release pharmaceutical granules and excipient granules to form a viscous oral pharmaceutical composition.

[0008] According to the present invention, an oral pharmaceutical composition prepared by mixing the pharmaceutical composition according to the present invention with water.

[0009] According to the present invention, a method for treating a disease in a patient, comprising orally administering a therapeutically effective amount of an oral pharmaceutical composition according to the present invention to a patient in need of such treatment.

[0010] Those skilled in the art will understand that the drawings provided herein are for illustrative purposes only. The drawings are not intended to limit the scope of this disclosure. [Brief explanation of the drawing]

[0011] [Figure 1] An example of a dissolution profile for immediate-release pharmaceutical granules is shown. [Figure 2] An example of a dissolution profile for a controlled-release pharmaceutical granule is shown. [Figure 3] Examples of dissolution profiles for pharmaceutical granules, including immediate-release and controlled-release pharmaceutical granules, are shown. [Figure 4] An example of the particle size distribution of excipient granules is shown. [Figure 5] Examples of the re-adjusted viscosity of solutions prepared using the excipient granules provided in this disclosure are shown. [Figure 6] This disclosure shows an example of the re-prepared brightness of a solution prepared using the excipient granules provided herein. [Figure 7] Examples of dissolution profiles for pharmaceutical compositions, including immediate-release pharmaceutical granules, controlled-release pharmaceutical granules, and excipient granules, are shown. [Figure 8] Examples of re-adjusted viscosities for pharmaceutical compositions, including immediate-release pharmaceutical granules, controlled-release pharmaceutical granules, and excipient granules, are shown. [Figure 9] This shows the γ-hydroxybutyrate plasma pharmacokinetic profiles after oral administration of different doses of oral pharmaceutical granules, including immediate-release and controlled-release pharmaceutical granules. [Figure 10]Figures A and B show the dissolution profiles of the pharmaceutical granules after storage at 5±3°C (Figure 9A) and 25±2°C / 60%RH (Figure 9B), as described in Example 6. [Figure 11] A and B show the dissolution profiles of the pharmaceutical composition, including the excipient granules and pharmaceutical granules, after storage at 5±3°C (Figure 10A) and 25±2°C / 60%RH (Figure 10B), as described in Example 6. [Modes for carrying out the invention]

[0012] For the purposes of the following detailed description, it should be understood that the embodiments provided by this disclosure may be subject to various alternative modifications and process sequences, unless expressly designated to be contrary. Furthermore, except for any embodiment of operation, or where otherwise shown, all numbers representing the quantities of components used in the specification and claims should be understood in all examples as being modified by the term “approximately.” Thus, unless shown to be contrary, the numerical parameters described in the following specification and appended claims are approximations that may vary depending on the desired characteristics obtained by the invention. At the very least, and without attempting to limit the application of the equivalent view to the scope of the claims, each numerical parameter should be interpreted in light of at least the reported number of significant figures and by applying the usual rounding techniques.

[0013] Although the numerical ranges and parameters describing the broad scope of this invention are approximations, the numerical values ​​described in specific examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error that inevitably arises from the standard deviation observed in each of its test measurements.

[0014] It should also be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of "1 to 10" includes all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, i.e., minimum values equal to or greater than 1 and maximum values equal to or less than 10.

[0015] "Immediate release" refers to a composition that releases at least 80% of 4-((L-valyl)oxy)butanoic acid within 1 hour when tested in a 0.1 N HCl dissolution medium at a temperature of 37 °C and a paddle speed of 75 rpm in dissolution apparatus 2 according to USP38.

[0016] An immediate release composition or formulation can release substantially all of the pharmacologically active ingredient into the patient's gastrointestinal tract within less than 1 hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. For example, an immediate release dosage form can release more than 90%, more than 95%, or more than 98% of a pharmacologically active ingredient such as 4-((L-valyl)oxy)butanoic acid in a pharmaceutical composition into the gastrointestinal tract within less than 1 hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. An immediate release pharmaceutical composition may be suitable for administering a pharmacologically active ingredient that is absorbed from the upper part of the gastrointestinal tract into the systemic circulation.

[0017] Examples of "modified release" pharmaceutical compositions and formulations include controlled release formulations, delayed release formulations, sustained release formulations, extended release formulations, timed release formulations, pulsatile release formulations, and pH-dependent release formulations. These formulations are intended to release the pharmacologically active ingredient from the pharmaceutical composition at a desired rate and / or at a desired time, and / or at a specific location or multiple locations within the gastrointestinal tract, and / or at a specific pH within the gastrointestinal tract, after oral administration by a patient. The United States Pharmacopeia (USP) defines a modified release system as one in which the time course or location, or both, of drug release are selected to achieve a therapeutic efficacy or convenience objective not met by an immediate release dosage form. Modified release oral dosage forms can include sustained release and delayed release components. Delayed release dosage forms do not release the drug immediately but release the drug in a single bolus at one time. Examples of modified release formulations include delayed release using an enteric coating, site-specific or timed release such as for colon delivery, for example, sustained release including formulations that can provide a zero-order, first-order, or biphasic release profile, and programmed release such as pulsatile release and delayed sustained release.

[0018] "Patient" refers to a mammal, such as a human.

[0019] "Pharmaceutically acceptable" refers to those that are approved or approvable by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia (USP), another generally recognized pharmacopeia for use in animals, more specifically in humans.

[0020] A "pharmaceutically acceptable salt" refers to a salt of a parent compound that has the desired pharmacological activity. Such salts include inorganic acids, as well as acid addition salts formed with one or more protonable prepared release groups, such as primary, secondary, or tertiary amines, in the parent compound. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts can be formed from organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc. Salts can be formed when one or more acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions, or combinations thereof, or by coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. A pharmaceutically acceptable salt may be a hydrochloride salt. A pharmaceutically acceptable salt may also be a sodium salt. In compounds having two or more ionizable groups, a pharmaceutically acceptable salt may contain one or more counterions, such as a dichloride salt.

[0021] The term “pharmaceutically acceptable salt” includes hydrates and other solvates, as well as salts in crystalline or amorphous forms. Where a particular pharmaceutically acceptable salt is disclosed, it should be understood that the particular salt (e.g., hydrochloride) is an example of a salt, and other salts may be formed using techniques known to those skilled in the art. In addition, using techniques generally known in the art, those skilled in the art may convert pharmaceutically acceptable salts to the corresponding compounds, free bases, and / or free acids.

[0022] A “prodrug” refers to a derivative of a drug molecule that requires conversion in the body to deliver an active drug. Prodrugs are often pharmacologically inactive until converted to the parent drug, though this is not always the case. Prodrugs can typically be obtained by attaching a pro-moiety (as defined herein) to a drug via a modulated release group.

[0023] To "cure" a disease means to eliminate the disease or disability, or to eliminate the symptoms of the disease or disability.

[0024] "Treating" or "treating" a disease or disorder means reducing the severity of one or more clinical symptoms of the disease or disorder, delaying the onset of one or more clinical symptoms of the disease or disorder, and / or alleviating one or more clinical symptoms of the disease or disorder. "Treating" or "treating" a disease or disorder means inhibiting one or more clinical symptoms of the disease or disorder, preventing the onset of one or more clinical symptoms of the disease or disorder, alleviating one or more clinical symptoms of the disease or disorder, causing regression of one or more clinical symptoms of the disease or disorder, and / or stabilizing one or more clinical symptoms of the disease or disorder. "Treating" or "treating" a disease or disorder means producing a clinically beneficial effect without curing the underlying disease or disorder.

[0025] The “therapeutic dose” refers to the amount of a pharmacologically active compound, such as 4-((L-valyl)oxy)butanoic acid or γ-hydroxybutyrate, that is sufficient to have such an effect on the treatment of the disease or at least one of its clinical symptoms when administered to a patient. The “therapeutic dose” may vary, for example, depending on the compound, the disease and / or symptoms of the disease, the severity of the disease and / or symptoms of the disease or disorder, the age, weight, and / or health of the patient being treated, and the judgment of the prescribing physician. The therapeutic dose in any given case may be determined by a person skilled in the art, by routine experimentation, or based on the judgment of the prescribing physician or healthcare professional.

[0026] The "therapeutic dose" refers to the dose that provides effective treatment for a disease or disorder in a patient. The therapeutic dose of 4-((L-valyl)oxy)butanoic acid or γ-hydroxybutyrate may vary from patient to patient and may depend on factors such as the patient's condition, the severity of the disease, and the route of delivery. The therapeutic dose may be determined according to routine pharmacological procedures known to those skilled in the art.

[0027] An "excipient" refers to a diluent, vehicle, or carrier administered to a patient along with a compound. An excipient can be a pharmaceutically acceptable vehicle. Pharmacologically acceptable excipients are known in the art.

[0028] The re-adjusted viscosity or viscosity of an aqueous solution prepared using excipient granules can be determined using a Brookfield Model LVDV-1+ digital viscometer equipped with a Brookfield SC4-18 spindle at a spindle speed of 30 RPM. Excipient granules, such as 1.2 g, can be added to water, such as 40 mL of water in a 50 mL beaker, and mixed for a specific time, such as 30, 60, 90, 120, 150, or 180 seconds. After stopping the mixing, the viscosity can be measured. The re-adjusted viscosity is typically measured at a temperature of 20°C to 25°C, such as 23°C.

[0029] The bulk density can be determined according to USP616, Method 1.

[0030] Tap bulk density can be determined according to USP616.

[0031] The specific surface area can be determined by laser diffraction.

[0032] Hausner ratio is USP <1174> It can be determined according to the following. The Hausner ratio is the ratio of tap density to bulk density.

[0033] The compressibility index is 100 × [(tap density - bulk density) / tap density].

[0034] The particle size distribution or average particle size of granules can be determined by laser diffraction or sieve analysis.

[0035] Flodex value is USP <1174> It can be determined accordingly.

[0036] Brightness can be determined using Technical Color Solutions' Datacolor 650® instrument.

[0037] Abrasion can be measured using an ultrasonic sieve. Abrasion is defined as the number of particles with a diameter of less than 75 μm produced by feeding granules through an ultrasonic sieve operated at an amplitude of 8 corresponding to 3,600 ultrasonic energy pulses per minute for at least 2 minutes.

[0038] "Pharmaceutical granules" refers to a group of pharmaceutical granules containing active pharmaceutical ingredients.

[0039] "Excipient granules" refers to a collection of multiple excipient granules that do not contain active pharmaceutical ingredients.

[0040] "Pharmaceutical composition" refers to a composition containing excipient granules and an active pharmaceutical ingredient. The active pharmaceutical ingredient may be in the form of pharmaceutical granules.

[0041] "Oral pharmaceutical composition" refers to a pharmaceutical composition intended to be taken orally by a patient.

[0042] Here, we refer to pharmaceutical compositions comprising pharmaceutical granules and excipient granules, as well as oral pharmaceutical compositions prepared using pharmaceutical granules. The disclosed pharmaceutical compositions and uses are not intended to limit the scope of the claims. On the contrary, the claims are intended to encompass all substitutes, modifications, and equivalents.

[0043] The pharmaceutical compositions provided by this disclosure include pharmaceutical granules and excipient granules. The pharmaceutical granules may include immediate-release pharmaceutical granules and controlled-release pharmaceutical granules.

[0044] A pharmaceutical composition comprising immediate-release granules and controlled-release granules can be independently supplied in one or more packages, such as one or more sachets or one or more stick packs.

[0045] When used, the contents of one or more packages containing immediate-release granules, controlled-release granules, and excipients can be mixed with water or an aqueous solution to provide a viscous solution containing at least partially dissolved immediate-release granules and controlled-release granules suspended in a viscous solution. A viscous solution containing the contents of completely dissolved excipient granules, at least partially dissolved immediate-release granules, and a suspension of controlled-release pharmaceutical granules provides an oral pharmaceutical composition suitable for oral intake by patients.

[0046] The pharmaceutical compositions provided by this disclosure may include immediate-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid or a pharmaceutically acceptable salt thereof, modified-release granules containing 4-((L-valyl)oxy)butanoic acid or a pharmaceutically acceptable salt thereof, and excipient granules.

[0047] The pharmaceutical compositions provided by this disclosure may include immediate-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid, adjusted-release granules containing 4-((L-valyl)oxy)butanoic acid, and excipient granules.

[0048] The pharmaceutical compositions provided by this disclosure may include immediate-release pharmaceutical granules containing crystalline 4-((L-valyl)oxy)butanoic acid, adjusted-release granules containing crystalline 4-((L-valyl)oxy)butanoic acid, and excipient granules.

[0049] The pharmaceutical composition may contain, for example, 1 g to 25 g of 4-((L-valyl)oxy)butanoic acid.

[0050] The pharmaceutical composition may contain, for example, 2% to 12% by weight of excipient granules, where the weight percentage is based on the total weight of the pharmaceutical composition.

[0051] The pharmaceutical composition may contain, for example, 86% to 98% by weight of pharmaceutical granules, where the weight percentage is based on the total weight of the pharmaceutical composition.

[0052] In a pharmaceutical composition, immediate-release pharmaceutical granules may contain 26% to 36% by weight of 4-((L-valyl)oxy)butanoic acid, and adjusted-release pharmaceutical granules may contain 64% to 74% by weight of 4-((L-valyl)oxy)butanoic acid, with the weight percentage being based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0053] In a pharmaceutical composition, the ratio of the weight of 4-((L-valyl)oxy)butanoic acid in the adjusted-release pharmaceutical granules to the weight of 4-((L-valyl)oxy)butanoic acid in the immediate-release pharmaceutical granules can be, for example, 1.7 to 3.7.

[0054] The pharmaceutical composition may include, for example, 15% to 35% by weight of immediate-release pharmaceutical granules, 55% to 75% by weight of controlled-release pharmaceutical granules, and 2% to 12% by weight of excipient granules, where the weight percentages are based on the total weight of the pharmaceutical composition.

[0055] The pharmaceutical composition may have a weight of, for example, 2g to 40g.

[0056] Immediate-release and regulated-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid or pharmaceutically acceptable salts thereof are disclosed, for example, in U.S. Patent Nos. 11,357,734 B2, 11,304,906 B2, 11,896,573 B2, 11,395,801 B2, and 11,510,892 B2, each of which is incorporated in whole by reference.

[0057] 4-((L-valyl)oxy)butanoic acid is a prodrug of γ-hydroxybutyrate. After oral administration, it is absorbed by the gastrointestinal tract and provides 4-((L-valyl)oxy)butanoic acid into the systemic circulation, where it is metabolized to provide γ-hydroxybutyrate into the patient's plasma. 4-((L-valyl)oxy)butanoic acid has the structure of formula (1): [ka]

[0058] 4-((L-valyl)oxy)butanoic acid is metabolized to provide 0.512 equivalents of γ-hydroxybutyric acid. The valylpro moiety stabilizes the otherwise cyclizable γ-hydroxybutyric acid.

[0059] 4-((L-valyl)oxy)butanoic acid may include crystalline 4-((L-valyl)oxy)butanoic acid, as disclosed in U.S. Publication No. 2024 / 0092727 A1. For example, crystalline 4-((L-valyl)oxy)butanoic acid can be characterized by an XRPD pattern containing characteristic diffraction peaks of at least 8.28°±0.20°, 16.75°±0.20°, and 25.33±0.20°, expressed as °2θ angles determined using Cu-Kα radiation, or by an XRPD pattern containing characteristic diffraction peaks of at least 8.28°±0.20°, 16.75°±0.20°, 17.64°±0.20°, 18.31°±0.20°, 19.42°±0.20°, 20.79°±0.20°, 25.33±0.20°, and 26.08°±0.20°, expressed as °2θ angles determined using Cu-Kα radiation.

[0060] As used herein, 4-((L-valyl)oxy)butanoic acid includes crystalline 4-((L-valyl)oxy)butanoic acid and pharmaceutically acceptable salts of 4-((L-valyl)oxy)butanoic acid.

[0061] The pharmaceutical granules may contain 1g to 20g of 4-((L-valyl)oxy)butanoic acid.

[0062] The pharmaceutical granules may include immediate-release pharmaceutical granules containing multiple immediate-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid, and adjusted-release pharmaceutical granules containing multiple adjusted-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid.

[0063] The pharmaceutical granules may include, for example, 17% to 37% by weight of immediate-release pharmaceutical granules and 63% to 83% by weight of controlled-release pharmaceutical granules, where the percentage by weight is based on the total weight of the pharmaceutical granules.

[0064] In pharmaceutical granules, immediate-release pharmaceutical granules may contain, for example, 2.5 g to 6.5 g of 4-((L-valyl)oxy)butanoic acid, while controlled-release pharmaceutical granules may contain 8 g to 12 g of 4-((L-valyl)oxy)butanoic acid.

[0065] Immediate-release pharmaceutical granules may contain multiple immediate-release pharmaceutical granules, which may be uncoated or coated with a seal coat.

[0066] Uncoated immediate-release pharmaceutical granules may contain, for example, more than 80% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentage is based on the total weight of the uncoated granules.

[0067] For example, uncoated immediate-release pharmaceutical granules may contain more than 80% by weight of 4-((L-valyl)oxy)butanoic acid, more than 85% by weight, more than 90% by weight, or more than 95% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentage is based on the total weight of the uncoated granules.

[0068] For example, uncoated immediate-release pharmaceutical granules may contain 80% to 98% by weight of 4-((L-valyl)oxy)butanoic acid, 80% to 95% by weight, 85% to 95% by weight, 81% to 97% by weight, 82% to 96% by weight, 83% to 95% by weight, 84% to 94% by weight, 85% to 93% by weight, or 84% to 92% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentage is based on the total weight of the uncoated granules.

[0069] Immediate-release pharmaceutical granules may, for example, contain a water-soluble polymer or a combination of water-soluble polymers.

[0070] Suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, povidone, crospovidone, and poloxamer.

[0071] The water-soluble polymer may include hydroxypropyl methylcellulose.

[0072] Uncoated immediate-release pharmaceutical granules may contain, for example, 1% to 9% by weight of a water-soluble polymer, 2% to 8% by weight, 3% to 7% by weight, 4% to 6% by weight, or about 5% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, where the weight percentage is based on the total weight of the uncoated granules.

[0073] Uncoated immediate-release pharmaceutical granules may contain, for example, less than 10% by weight of water-soluble polymer, less than 8% by weight, less than 6% by weight, less than 4% by weight, or less than 2% by weight of water-soluble polymer, where the weight percentage is based on the total weight of the uncoated granules.

[0074] Uncoated immediate-release pharmaceutical granules may contain, for example, an antistatic agent or a combination of antistatic agents.

[0075] Suitable examples of antistatic agents include talc (hydrated magnesium silicate), magnesium stearate, and silicon dioxide.

[0076] The antistatic agent may contain hydrated magnesium silicate (talc).

[0077] Uncoated immediate-release pharmaceutical granules may contain, for example, 1% to 9% by weight of an antistatic agent, 2% to 8% by weight, 3% to 7% by weight, 4% to 6% by weight, or about 5% by weight of an antistatic agent such as hydrated magnesium silicate, where the percentage by weight is based on the total weight of the uncoated immediate-release pharmaceutical granules.

[0078] Uncoated immediate-release pharmaceutical granules may contain, for example, 85% to 95% by weight of 4-((L-valyl)oxy)butanoic acid, 1% to 9% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, and 1% to 9% by weight of an antistatic agent such as hydrated magnesium silicate, where the weight percentage is based on the total weight of the uncoated immediate-release pharmaceutical granules.

[0079] Uncoated immediate-release pharmaceutical granules may contain, for example, 88% to 92% by weight of 4-((L-valyl)oxy)butanoic acid, 3% to 7% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, and 3% to 7% by weight of an antistatic agent such as hydrated magnesium silicate, where the weight percentage is based on the total weight of the uncoated immediate-release pharmaceutical granules.

[0080] Uncoated immediate-release pharmaceutical granules may contain, for example, 89% to 91% by weight of 4-((L-valyl)oxy)butanoic acid, 4% to 6% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, and 4% to 6% by weight of an antistatic agent such as hydrated magnesium silicate, where the weight percentage is based on the total weight of the uncoated immediate-release pharmaceutical granules.

[0081] Uncoated immediate-release pharmaceutical granules may contain, for example, about 90% by weight of 4-((L-valyl)oxy)butanoic acid, about 5% by weight of a water-soluble polymer such as hydroxypropyl methylcellulose, and about 5% by weight of an antistatic agent such as hydrated magnesium silicate, where the weight percentage is based on the total weight of the uncoated immediate-release pharmaceutical granules.

[0082] Uncoated immediate-release pharmaceutical granules can have a homogeneous composition throughout the entire uncoated granule.

[0083] Uncoated immediate-release pharmaceutical granules can have average granule sizes of, for example, 100 μm to 600 μm, 150 μm to 550 μm, 200 μm to 500 μm, 250 μm to 450 μm, or 300 μm to 400 μm, where the average granule size is determined by sieve analysis or laser diffraction.

[0084] Uncoated immediate-release pharmaceutical granules can have, for example, average granule sizes greater than 100 μm, 200 μm, 300 μm, 400 μm, or 500 μm, and the average granule size is determined by sieve analysis or laser diffraction.

[0085] Uncoated immediate-release pharmaceutical granules may have an average granule size of, for example, less than 600 μm, less than 500 μm, less than 400 μm, less than 300 μm, or less than 200 μm, and the average granule size may be determined by sieve analysis or laser diffraction.

[0086] Uncoated immediate-release pharmaceutical granules can have bulk densities of, for example, greater than 0.40 g / mL, greater than 0.50 g / mL, greater than 0.60 g / mL, greater than 0.90 g / mL, greater than 1.10 g / mL, greater than 1.30 g / mL, or greater than 1.50 g / mL, and the bulk density is determined using a bulk density cylinder.

[0087] Uncoated immediate-release pharmaceutical granules can have bulk densities of, for example, 0.40 g / mL to 1.60 g / mL, 0.40 g / mL to 1.20 g / mL, 0.40 g / mL to 0.80 g / mL, 0.50 g / mL to 1.60 g / mL, 0.50 g / mL to 1.40 g / mL, 0.50 g / mL to 1.20 g / mL, 0.60 g / mL to 1.60 g / mL, 0.70 g / mL to 1.50 g / mL, 0.80 g / mL to 1.40 g / mL, or 1.00 g / mL to 1.20 g / mL, which are determined using a bulk density cylinder.

[0088] Uncoated immediate-release pharmaceutical granules can have bulk densities of, for example, 0.60 g / mL to 1.60 g / mL, 0.70 g / mL to 1.50 g / mL, 0.80 g / mL to 1.40 g / mL, or 1.00 g / mL to 1.20 g / mL, and the bulk density is determined using a bulk density cylinder.

[0089] Uncoated immediate-release pharmaceutical granules or granules can have bulk densities of, for example, 0.5 g / mL to 1.0 g / mL, 0.5 g / mL to 0.9 g / mL, 0.5 g / mL to 0.8 g / mL, 0.5 g / mL to 0.7 g / mL, or 0.6 g / mL to 0.7 g / mL. Uncoated pharmaceutical granules or granules can have bulk densities of, for example, greater than 0.5 g / mL, greater than 0.6 g / mL, greater than 0.7 g / mL, greater than 0.8 g / mL, or greater than 0.9 g / mL, and the bulk density is determined using a bulk density cylinder.

[0090] Uncoated immediate-release pharmaceutical granules may include multiple granules characterized by mode sphericity of 0.90 to 1, such as 0.91 to 0.99 or 0.92 to 0.98, where sphericity is determined using a wet dispersion particle shape method or by dynamic image analysis. Uncoated immediate-release pharmaceutical granules provided by this disclosure may include multiple granules characterized by mean sphericity of greater than 0.94, greater than 0.95, greater than 0.96, greater than 0.97, greater than 0.98, or greater than 0.99.

[0091] The uncoated immediate-release pharmaceutical granules provided by this disclosure may feature, for example, abrasion values ​​of 0% to 2%. Granules with lower abrasion are easier to coat than granules with higher abrasion. Abrasion is defined as the amount of granules having a diameter of less than 75 μm produced by subjecting the granules to an ultrasonic sieve operated at an amplitude of 8 corresponding to 3,600 ultrasonic energy pulses per minute for at least 2 minutes. The uncoated immediate-release pharmaceutical granules provided by this disclosure may feature, for example, abrasion values ​​of less than 2%, less than 1.8%, less than 1.6%, less than 1.4%, less than 1.2%, less than 1.0%, less than 0.8%, less than 0.6%, less than 0.4%, or less than 0.2%. The immediate-release pharmaceutical granules provided by this disclosure may have, for example, an abrasion of 1.02%, and the abrasion is determined using an ultrasonic sieve.

[0092] Uncoated immediate-release pharmaceutical granules can be completely dissolved in water in less than 5 minutes, such as less than 4 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute, after mixing and stirring in water. Immediate-release pharmaceutical granules can be at least partially dissolved in water in less than 5 minutes, such as less than 4 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute, after mixing and stirring in water.

[0093] Uncoated immediate-release pharmaceutical granules may feature a solubility profile in a buffered aqueous solution with a pH of 4.0 to 5.0 at a temperature of 20°C to 25°C, such as 23°C, where 80% by weight of the granules dissolves within 0.5 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, or 5 minutes.

[0094] Figure 1 shows an example of a dissolution profile for uncoated immediate-release pharmaceutical granules.

[0095] Immediate-release pharmaceutical granules can be coated with a seal coat.

[0096] The seal coating can enhance the storage stability of coated microparticles by minimizing the penetration of moisture into the pharmacologically active ingredient, thereby reducing the hydrolysis of the pharmacologically active ingredient. The seal coating can also enhance the storage stability of coated microparticles by minimizing negative interactions between the controlled-release coating and the pharmacologically active ingredient, thereby reducing the hydrolysis of 4-((L-valyl)oxy)butanoic acid.

[0097] The seal coating may include, for example, water-soluble polymers such as hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol.

[0098] The seal coating may have an average thickness of, for example, 0.5 μm to 5 μm, 1 μm to 4 μm, or 1 μm to 3 μm. The seal coating may have an average thickness of, for example, less than 5 μm, less than 4 μm, less than 3 μm, less than 2 μm, or less than 1 μm.

[0099] Coated immediate-release pharmaceutical granules may not dissolve completely after mixing with water for longer than 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, or 10 minutes.

[0100] Uncoated immediate-release drug granules have a dissolution profile as shown in Figure 1. Uncoated immediate-release drug granules have a dissolution profile that is biologically equivalent to the dissolution profile shown in Figure 1.

[0101] A modified-release granule may contain multiple modified-release pharmaceutical granules. A modified-release pharmaceutical granule may contain one or more modified-release pharmaceutical granules, and the different granules may have different compositions and / or properties, such as average granule size, active pharmaceutical ingredient, release profile, and / or excipient composition. Each of the two or more modified-release pharmaceutical granules may have a different release profile in the gastrointestinal tract. A modified-release pharmaceutical granule may contain uncoated or coated immediate-release pharmaceutical granules together with a modified-release coating surrounding the uncoated immediate-release pharmaceutical granules. A modified-release pharmaceutical granule may contain uncoated immediate-release pharmaceutical granules together with a modified-release coating surrounding the uncoated immediate-release pharmaceutical granules.

[0102] The adjusted-release pharmaceutical granules may contain, for example, 70% to 90% by weight of immediate-release pharmaceutical granules, 76% to 86% by weight, 77% to 85% by weight, 78% to 84% by weight, 79% to 83% by weight, 70% to 82% by weight, or 80.65% by weight of an immediate-release core, where the weight percentage is based on the total weight of the adjusted-release pharmaceutical granules.

[0103] Adjusted-release pharmaceutical granules may include, for example, over 65% by weight of immediate-release pharmaceutical granules, over 70% by weight, over 75% by weight, over 80% by weight, over 85% by weight, over 90% by weight, or over 95% by weight of immediate-release pharmaceutical granules, where the weight percentage is based on the total weight of the adjusted-release pharmaceutical granules.

[0104] The controlled-release pharmaceutical granules may contain, for example, 5% to 40% by weight of the controlled-release coating, 10% to 35% by weight, 10% to 30% by weight, 14% to 24% by weight, 15% to 23% by weight, 16% to 22% by weight, 17% to 21% by weight, 18% to 20% by weight, or about 19% by weight of the controlled-release coating, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0105] The controlled-release pharmaceutical granules may include, for example, less than 30% by weight of the controlled-release coating, less than 25% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, or less than 5% by weight of the controlled-release coating, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0106] The regulated-release pharmaceutical granules may include, for example, 75% to 85% by weight of immediate-release pharmaceutical granules and 15% to 25% by weight of regulated-release coating, where the weight percentage is based on the total weight of the regulated-release pharmaceutical granules.

[0107] The controlled-release pharmaceutical granules may, for example, consist of 77% to 83% by weight of immediate-release pharmaceutical granules and 17% to 23% by weight of controlled-release coating, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0108] The regulated release pharmaceutical granules may contain, for example, 65% to 85% by weight of 4-((L-valyl)oxy)butanoic acid, 68% to 78% by weight, 69% to 77% by weight, 70% to 76% by weight, 71% to 75% by weight, 72% to 74% by weight, or about 73% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentage is based on the total weight of the regulated release pharmaceutical granules.

[0109] The controlled release coating may include water-insoluble polymers, water-soluble polymers, lubricants, antistatic agents, or any combination thereof.

[0110] The controlled release coating may include a water-insoluble polymer or a combination of water-insoluble polymers.

[0111] Suitable examples of water-insoluble polymers include ethylcellulose, as well as polyvinyl acetate, polyacrylate, and polymethacrylate.

[0112] The water-insoluble polymer may contain ethylcellulose.

[0113] The controlled release coating may contain, for example, 68% to 78% by weight of a water-insoluble polymer such as ethylcellulose, 67% to 77% by weight, 68% to 76% by weight, or 69% to 75% by weight of a water-insoluble polymer such as ethylcellulose, where the weight percentage is based on the total weight of the controlled release coating.

[0114] The controlled release coating may include a water-soluble polymer or a combination of water-soluble polymers.

[0115] Suitable water-soluble polymers include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol.

[0116] The water-soluble polymer may contain hydroxypropylcellulose.

[0117] The controlled release coating may contain, for example, 2% to 6% by weight of a water-soluble polymer such as hydroxypropyl cellulose, 2.5% to 5.5% by weight, 3% to 5% by weight, or 3.5% to 4.5% by weight of a water-soluble polymer such as hydroxypropyl cellulose, where the weight percentage is based on the total weight of the controlled release coating.

[0118] The controlled release coating may contain a plasticizer or a combination of plasticizers.

[0119] Examples of suitable plasticizers include dibutyl sebacate, polyethylene glycol, triacetin, and triethyl citrate.

[0120] The plasticizer may include dibutyl sebacate.

[0121] The adjusted release coating may contain, for example, 4% to 12% by weight of a plasticizer such as dibutyl sebacate, 5% to 10% by weight, 6% to 9% by weight, or 6% to 8% by weight of a plasticizer such as dibutyl sebacate, where the weight percentage is based on the total weight of the adjusted release coating.

[0122] The controlled emission coating may include an antistatic agent or a combination of antistatic agents.

[0123] Suitable examples of antistatic agents include talc (hydrated magnesium silicate), magnesium stearate, sodium stearyl fumarate, and silicon dioxide.

[0124] The antistatic agent may contain hydrated magnesium silicate (talc).

[0125] The controlled release coating may contain, for example, 10% to 20% by weight of an antistatic agent such as hydrated magnesium silicate (talc), 11% to 19% by weight, 12% to 18% by weight, 13% to 17% by weight, or 14% to 16% by weight of an antistatic agent such as hydrated magnesium silicate (talc), where the weight percentage is based on the total weight of the controlled release coating.

[0126] The controlled release coating may include, for example, water-insoluble polymers, water-soluble polymers, lubricants, and antistatic agents.

[0127] The regulated release coating may contain 63% to 83% by weight of a water-insoluble polymer, 2% to 10% by weight of a water-soluble polymer, 6% to 10% by weight of a lubricant, and 10% to 20% by weight of an antistatic agent, where the weight percentages are based on the total weight of the regulated release coating.

[0128] In controlled-release pharmaceutical granules or controlled-release coatings, the water-insoluble polymer may include ethylcellulose, the water-soluble polymer may include hydroxypropylcellulose, the lubricant may include dibutyl sebacate, and the antistatic agent may include hydrated magnesium silicate.

[0129] The adjusted-release pharmaceutical granules may contain, for example, 11% to 17% by weight of a water-insoluble polymer such as ethylcellulose, 12% to 16% by weight, 13% to 15% by weight, or 14.14% by weight of a water-insoluble polymer such as ethylcellulose, where the weight percentage is based on the total weight of the adjusted-release pharmaceutical granules.

[0130] The controlled-release pharmaceutical granules may contain, for example, 0.45% to 1.05% by weight of a water-soluble polymer such as hydroxypropyl cellulose, 0.55% to 0.95% by weight, 0.65% to 0.85% by weight, 0.70% to 0.80% by weight, or 0.75% by weight of a water-soluble polymer such as hydroxypropyl cellulose, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0131] The controlled-release pharmaceutical granules may contain, for example, 0.5% to 2.5% by weight of a plasticizer such as dibutyl sebacate, 0.75% to 2.25% by weight, 1.0% to 2.0% by weight, or 1.25% to 1.75% by weight of a plasticizer such as dibutyl sebacate, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0132] The controlled-release pharmaceutical granules may contain, for example, 1.0% to 5.0% by weight of an antistatic agent such as hydrated magnesium silicate (talc), 1.5% to 4.5% by weight, 2.0% to 4.0% by weight, 2.5% to 3.5% by weight, or 2.8% to 3.2% by weight of an antistatic agent such as hydrated magnesium silicate (talc), where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0133] The adjusted-release pharmaceutical granules may contain, for example, 70% to 90% by weight of uncoated immediate-release pharmaceutical granules, 11% to 17% by weight of a water-insoluble polymer such as ethylcellulose, 0.45% to 1.05% by weight of a water-soluble polymer such as hydroxypropylcellulose, 0.5% to 2.5% by weight of a lubricant such as dibutyl sebacate, and 1.0% to 5.0% by weight of an antistatic agent such as hydrated magnesium silicate (talc), where the weight percentages are based on the total weight of the adjusted-release pharmaceutical granules.

[0134] The controlled emission coating can have thicknesses of, for example, 5 μm to 40 μm, 5 μm to 30 μm, 5 μm to 20 μm, 5 μm to 10 μm, 10 μm to 40 μm, 10 μm to 30 μm, or 10 μm to 20 μm.

[0135] The controlled emission coating can have a thickness of, for example, less than 50 μm, less than 40 μm, less than 30 μm, less than 20 μm, or less than 10 μm.

[0136] The controlled-release pharmaceutical granules may contain, for example, 10% to 45% by weight, 10% to 40% by weight, or 10% to 30% by weight of a controlled-release coating, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0137] The controlled-release pharmaceutical granules may contain, for example, less than 45% by weight, less than 40% by weight, less than 35% by weight, less than 320% by weight, less than 25% by weight, less than 20% by weight, or less than 15% by weight of the controlled-release coating, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0138] Adjusted-release pharmaceutical granules can have average granule sizes of, for example, 100 μm to 600 μm, 150 μm to 550 μm, 200 μm to 500 μm, 250 μm to 450 μm, or 300 μm to 400 μm, and the average granule size is determined by sieve analysis or laser diffraction.

[0139] The controlled-release pharmaceutical granules may have an average granule size of, for example, more than 100 μm, more than 200 μm, more than 300 μm, more than 400 μm, or more than 500 μm, and the average granule size is determined by sieve analysis or laser diffraction.

[0140] The controlled-release pharmaceutical granules may have an average granule size of, for example, less than 600 μm, less than 550 μm, less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, or less than 250 μm, and the average granule size is determined by sieve analysis or laser diffraction.

[0141] The controlled-release pharmaceutical granules provided by this disclosure may have, for example, average bulk densities of 0.4 g / mL to 1.60 g / mL, 0.40 g / mL to 1.40 g / mL, 0.50 g / mL to 0.90 g / mL, 0.55 g / mL to 0.80 g / mL, 0.60 g / mL to 75 g / mL, or 0.60 g / mL to 0.70 g / mL. The controlled-release pharmaceutical granules may have bulk densities greater than 0.50 g / mL, greater than 0.60 g / mL, greater than 0.80 g / mL, greater than 0.90 g / mL, greater than 1.00 g / mL, greater than 1.20 g / mL, or greater than 1.40 g / mL, and the bulk density may be determined using a bulk density cylinder. The controlled-release pharmaceutical granules may have a bulk density of, for example, less than 1.6 g / mL, less than 1.20 g / mL, less than 1.00 g / mL, less than 0.80 g / mL, or less than 0.60 g / mL, and the bulk density is determined using a bulk density cylinder.

[0142] The controlled-release pharmaceutical granules may have a water content of, for example, less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.5% by weight, or less than 0.25% by weight, where the weight percentage is based on the total weight of the controlled-release pharmaceutical granules.

[0143] The controlled-release pharmaceutical granules may have a water content of, for example, 0.1% to 2% by weight, 0.1% to 1% by weight, or 0.2% to 0.5% by weight, where the percentage by weight is based on the total weight of the controlled-release pharmaceutical granules.

[0144] The controlled-release pharmaceutical granules can be configured to continuously release 4-((L-valyl)oxy)butanoic acid over time within the gastrointestinal tract.

[0145] The controlled-release pharmaceutical granules may have a solubility profile in a buffered aqueous solution at pH 6.8 at a temperature of 23°C, characterized by 20% to 40% solubility in 1 hour, 50% to 70% in 2 hours, 60% to 80% in 3 hours, 70% to 90% in 5 hours, and / or over 80% in 6 hours.

[0146] The controlled-release pharmaceutical granules may have a solubility profile in a buffered aqueous solution at pH 6.8 at a temperature of 23°C, characterized by 25% to 35% solubility in 1 hour, 55% to 65% in 2 hours, 65% to 75% in 3 hours, 75% to 85% in 5 hours, and / or over 80% solubility in 6 hours.

[0147] The controlled-release pharmaceutical granules can have a solubility profile in a buffered aqueous solution with a pH of 6.8 at a temperature of 23°C, as shown in Figure 2.

[0148] The controlled-release pharmaceutical granules may have a solubility profile in a buffered aqueous solution at a temperature of 23°C and a pH of 6.8, which is biologically equivalent to the solubility profile shown in Figure 2.

[0149] The pharmaceutical granules provided by this disclosure may have an average bulk density of, for example, 0.6 g / mL to 0.9 g / mL, 0.65 g / mL to 0.85 g / mL, or 0.7 g / mL to 0.8 g / mL, where the average granule bulk density is determined using a bulk density cylinder.

[0150] The pharmaceutical granules provided by this disclosure may have an average tap density of, for example, within ±20% of the average tap density of the excipient granules to which the pharmaceutical granules are combined, within ±15%, within ±10%, or within ±5% of the average tap density of the excipient granules to which the pharmaceutical granules are combined, and the average granule tap density is subject to USP <616> It is determined according to the following.

[0151] The pharmaceutical granules provided by this disclosure may have, for example, an average tap density of 500 g / mL to 900 g / mL, 550 g / mL to 850 g / mL, 600 g / mL to 800 g / mL, or 650 g / mL to 750 g / mL, and the average granule tap density is subject to USP standards. <616> It is determined according to the following.

[0152] The pharmaceutical granules provided by this disclosure may have a Hausner ratio that is, for example, within ±20% of the average Hausner ratio of the excipient granules to which the pharmaceutical granules are combined, within ±15%, within ±10%, or within ±5% of the Hausner ratio of the excipient to which the pharmaceutical granules are combined, and the Hausner ratio is as defined in the USP <1174> It is determined according to the following.

[0153] The pharmaceutical granules provided by this disclosure may have Hausner ratios of, for example, 1.0–1.5, 1.1–1.4, 1.1–1.35, or 1.1–1.25, and the Hausner ratio is defined in the USP <1174> It is determined according to the following.

[0154] The pharmaceutical granules provided by this disclosure may have a compressibility index of, for example, within ±20% of the compressibility index of the excipient granules to which the pharmaceutical granules are combined, within ±15%, within ±10%, or within ±5% of the compressibility index of the excipient granules to which the pharmaceutical granules are combined.

[0155] The pharmaceutical granules provided by this disclosure may have, for example, a compressibility index of 8 to 22, 10 to 20, or 12 to 18.

[0156] The pharmaceutical granules provided by this disclosure may have a Flodex value that is, for example, within ±20% of the Flodex value of the excipient granules to which the pharmaceutical granules are combined, within ±15%, within ±10%, or within ±5% of the Flodex value of the excipient granules to which the pharmaceutical granules are combined, and the Flodex value is subject to USP <1174> It is determined according to the following.

[0157] The pharmaceutical granules provided by this disclosure may have, for example, a Flodex value of less than 5 mm, less than 4 mm, less than 3 mm, or less than 2 mm, and the Flodex value is a USP <1174> It is determined according to the following.

[0158] The pharmaceutical granules provided by this disclosure may have a degree of abrasion of less than 0.2, for example, about 0.1, and the degree of abrasion is determined using an ionic sieve.

[0159] The pharmaceutical compositions provided by this disclosure may include excipient granules or combinations of excipient granules.

[0160] The excipient granules provided by this disclosure can improve the taste of orally administered pharmaceutical granules.

[0161] Taste can be defined as the overall flavor of an oral drug, relating to its smell, taste, aftertaste, and texture or feel in the mouth. Taste includes the overall acceptability of the taste, flavor, and smell of a drug administered orally and / or swallowed, as well as its volume or size and texture. The excipient granules provided by this disclosure can increase the viscosity of an orally administered solution containing the pharmaceutical granules, thereby reducing a rough or gritty feeling in the mouth.

[0162] To improve convenience during use, the excipient granules can provide a viscous solution that allows the pharmaceutical granules to be suspended within 30 seconds after being mixed with water.

[0163] The optimal solution viscosity can be determined by numerous factors, including the density of the pharmaceutical granules, the average size of the granules, the size distribution of the granules, and the average volume of the granules.

[0164] The excipient granules provided by this disclosure may be particularly useful with high-dose drugs. High-dose drugs may require administration in the form of large tablets or multiple tablets. The inconvenience and / or discomfort of administering high-dose drugs in tablet form can be avoided by using pharmaceutical granules. However, high-dose granules may produce a rough or gritty sensation in the mouth.

[0165] For convenience, it is desirable that the viscous solution prepared using the excipient granules provided herein be potable. The potable solution should be prepared at a temperature of 20°C to 25°C, such as 23°C, according to USP standards. <912> The viscosity can be, for example, 50 cP to 500 cP, determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. The excipient granules provided by this disclosure, when mixed with 40 mL of water at 23°C, have a USP <912> It can be configured to provide a viscosity of, for example, 20 cP to 100 cP, determined using a No. 62 spindle at a speed of 12 rpm according to method 1c.

[0166] However, it is also possible to provide pharmaceutical compositions with higher viscosity that are more readily consumed by using excipient granules. For example, the pharmaceutical composition can be fermented at temperatures of 20°C to 25°C, such as 23°C, using USP <912> The viscosity can be 100 cP to 500 cP, as determined using a No. 62 spindle at a speed of 12 rpm according to method 1c.

[0167] The intended purposes of the excipient granules provided by this disclosure include, for example, (1) providing a viscous solution having a viscosity of 10 cP to 200 cP, such as 40 cP to 80 cP or 50 cP to 70 cP, after mixing with an aqueous solution at 23°C in less than 90 seconds, such as less than 30 seconds; (2) providing an average excipient granule size similar to that of pharmaceutical granules; (3) providing excipient granules that are physically robust for storage and transport; and (4) providing a homogeneous granular composition such that the excipient granules and other granules, such as controlled-release pharmaceutical granules, do not separate in the composition and remain homogeneously dispersed throughout the suspension. It is desirable that the excipient granules and other granules in the composition remain homogeneously dispersed to facilitate the ability of the re-prepared solution and / or suspension to be homogeneous. Additional intended purposes may include (1) improved taste, (2) pH maintenance, (3) rapid dissolution, and (4) low weight % or low volume.

[0168] In the oral pharmaceutical composition provided in this disclosure, the oral pharmaceutical composition is mixed with 40 mL of water at 23°C for 30 seconds, and then USP <912> The viscosity can be 60 cP to 600 cP, for example, 200 cP to 600 cP, 300 cP to 600 cP, etc., determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. In the oral pharmaceutical composition provided by this disclosure, the oral pharmaceutical composition is mixed with 40 mL of water at 23°C for 60 seconds, and then USP <912> The viscosity can be 200 cP to 1,100 cP, for example, 400 cP to 1,000 cP, or 600 cP to 1,000 cP, as determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. The oral pharmaceutical composition can have a viscosity similar to that of a drinkable yogurt product.

[0169] In the oral pharmaceutical composition provided in this disclosure, the oral pharmaceutical composition is mixed with 40 mL of water at 23°C for 15 to 45 seconds, and then USP <912> The viscosity can be 60 cP to 600 cP, for example, 200 cP to 600 cP, 300 cP to 600 cP, etc., determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. In the oral pharmaceutical composition provided by this disclosure, the oral pharmaceutical composition is mixed with 40 mL of water at 23°C for 45 to 75 seconds, and then USP <912> The viscosity can be 200 cP to 1,100 cP, for example, 400 cP to 1,000 cP, 600 cP to 1,000 cP, etc., as determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. The oral pharmaceutical composition can have a viscosity similar to that of a drinkable yogurt product.

[0170] In addition to excipient granules, the viscosity of oral pharmaceutical formulations is determined by the dissolution of immediate-release pharmaceutical granules and by the suspended adjusted-release pharmaceutical granules.

[0171] The excipient granules provided by this disclosure comprise a plurality of excipient granules. The excipient granules provided by this disclosure may contain pharmaceutically acceptable excipients.

[0172] Excipient granules, when combined with water, provide a viscous aqueous solution. The viscosity of the viscous aqueous solution can be selected to improve the palatability of the pharmaceutical composition containing pharmaceutical granules dispersed and suspended in the viscous solution. A suitable viscosity effective in improving the palatability of pharmaceutical granules may depend, for example, on the average size of the pharmaceutical granules, the size distribution of the pharmaceutical granules, the density of the pharmaceutical granules, the volume percentage of the pharmaceutical granules in the viscous aqueous solution, or any combination of the above. Generally, it is desirable that the viscosity of an oral pharmaceutical composition for administration to a patient be drinkable. A drinkable composition may have a viscosity similar to, for example, drinkable yogurt. For example, a drinkable composition may be a USP <912> The viscosity can be 50 cp to 600 cP, as determined using a No. 62 spindle at a speed of 12 rpm according to method 1c.

[0173] The excipient granules provided by this disclosure may include a viscous agent, a disintegrant, and one or more additional excipients.

[0174] The excipient granules provided by this disclosure may include amounts of each excipient suitable for achieving the intended purpose of the excipient granules, such as improving the taste of the pharmaceutical granules.

[0175] The excipient granules provided by this disclosure can provide a viscous solution within 90 seconds, such as within 30 seconds, when combined and mixed with an aqueous solution at a temperature of 20°C to 25°C, such as 23°C. The maximum viscosity of the aqueous solution at a temperature of 20°C to 25°C, such as 23°C, can be, for example, 10 cP to 200 cP, 25 cP to 150 cP, 50 cP to 100 cP, 40 cP to 80 cP, or 50 cP to 70 cP.

[0176] When combined with an aqueous solution, the excipient granules can provide a viscous solution containing pharmaceutical granules dispersed and suspended in a palatable viscous solution for oral administration. Additional excipients to the excipient granules provided by this disclosure may be selected, for example, to reduce the granular texture of the pharmaceutical granules and to improve the taste of the pharmaceutical composition. Additional excipients may be selected to adjust the pH of the pharmaceutical composition and to improve the storage stability of the excipient granules and / or pharmaceutical granules.

[0177] The excipient granules provided by this disclosure may include, for example, a viscous agent, a disintegrant, and one or more additional excipients. The one or more additional excipients are added to the viscous agent and the disintegrant.

[0178] The excipient granules provided by this disclosure may include a viscous agent or a combination of viscous agents. The viscous agent may be a pharmaceutically acceptable viscous agent.

[0179] Viscosity-enhancing agents can be used to increase the viscosity of liquid compositions, such as aqueous compositions containing oral pharmaceutical compositions.

[0180] For example, when excipient granules are mixed with water at a concentration of 0.01 g / mL to 0.04 g / mL, a solution with a viscosity greater than 20 cP, greater than 30 cP, greater than 40 cP, greater than 50 cP, greater than 60 cP, greater than 70 cP, greater than 80 cP, greater than 90 cP, or greater than 100 cP can be provided in less than 2 minutes while stirring, mixing, and / or shaking at a temperature of 20°C to 25°C such as 23°C. <912> This method provides solutions with viscosities ranging from 20 cP to 100 cP, such as 40 cP to 80 cP, determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c.

[0181] Suitable viscosifying agents include, for example, plant extracts such as starch, pectin, alginates, carrageenan, acacia gum, tragacanth, and cellulose; modified polysaccharides such as modified starch, amidated pectin, and propylene glycol alginate; cellulose ethers such as microcrystalline cellulose, hypromellose, hydroxypropyl cellulose, and carboxymethyl cellulose; animal extracts such as gelatin, chitosan, and caseinates; fermentation products such as xanthan gum, gelan gum, pullulan, and dextran; seed polysaccharides such as guar gum and locust bean extract, as well as any combination of the above.

[0182] The viscosity-enhancing agents may include, for example, hydrocolloidal gums containing plant-derived hydrocolloids such as pectin, agar, alginate, acacia, tragacanth, karaya gum, guar gum, starch, cellulose, and locust bean; fermentation hydrocolloid products such as xanthan gum, dextran, gelan gum, and pullulan; semi-synthetic hydrocolloids containing cellulose ethers (such as modified starch, methylcellulose, hypromellose, ethylcellulose, hydroxypropylcellulose, and hydroxyethylcellulose), amidated pectin, and propylene glycol alginate; animal-derived hydrocolloids such as gelatin, chitosan, and caseinate, as well as any combination of the above.

[0183] The viscosifying agent may include bentonite, hectorite, and aluminum silicate such as magnesium aluminum silicate.

[0184] The viscosifying agent may include carbomer.

[0185] The viscosifying agent may include polyols, sugars, sorbitol, liquid maltitol, sucrose, fructose, dextrose, maltodextrin, and oligosaccharides such as polydextrose.

[0186] Other suitable viscosifiers include polyethylene glycol, polyethylene oxide, colloidal silicon dioxide, silicone, glycerin, fatty acids, and hard fats.

[0187] The viscosifying agent may include water-soluble polyvinylpyrrolidones such as povidone and crospovidone having an average molecular weight of 2,500 g / mol to 1,250,000 g / mol; ethylene vinyl acetate; and vinyl polymers such as polyvinyl alcohol having a degree of hydrolysis of over 88% and a molecular weight of 20,000 g / mol to 100,000 g / mol.

[0188] Suitable viscosifying agents include, for example, guar gum, xanthan gum, sodium carboxymethylcellulose, and any combination of the above.

[0189] The viscosity agent may be in the form of particles, and the particles may have an average particle size of less than 75 μm, less than 50 μm, or less than 25 μm. For example, the particles of the viscosity agent may have an average particle size of 10 μm to 75 μm, 20 μm to 70 μm, or 25 μm to 65 μm. Viscosity agents such as xanthan gum may have an average particle size of less than 75 μm.

[0190] The viscosifying agent may include xanthan gum such as Xnatural® 75, available from CP Kelco.

[0191] When determined using screen sieving, for example, a viscous agent such as xanthan gum can have a particle size in which 100% or more passes through an 80-mesh (180 μm) screen, such as 92% or more passing through a 200-mesh (75 μm) screen. A viscous agent such as xanthan gum can have a loss on drying (LOD) of 15% or less. When determined using transmittance, a viscous agent such as xanthan gum can provide a viscosity of, for example, 1,200 mPa×s to 1,600 mPa×s with 1% by weight of the viscous agent in a 1% KCl solution at 60 rpm. A viscous agent such as xanthan gum can provide a viscosity ratio of, for example, 1.02 to 1.45. When determined using transmittance, a viscous agent such as xanthan gum can provide a solution pH of, for example, 6.0 to 8.0 with 1% by weight of the viscous agent in distilled water.

[0192] The excipient granules may contain, for example, 1% to 40% by weight of a viscous agent, 1% to 35% by weight, 1% to 30% by weight, 1% to 20% by weight, 5% to 15% by weight, or 8% to 12% by weight of a viscous agent, where the weight percentage is based on the total weight of the excipient granules.

[0193] The excipient granules provided by this disclosure may include a disintegrant or a combination of disintegrants. The disintegrant may be a pharmaceutically acceptable disintegrant.

[0194] The disintegrant, after being mixed with an aqueous solution at a temperature of 20°C to 25°C, promotes the rapid disintegration, decomposition, and dissolution of the excipient granules.

[0195] It is desirable that the excipient granules be mixed in an aqueous solution at a temperature of 20°C to 25°C (such as 23°C) and then completely dissolve in water within 30 seconds, 60 seconds, 90 seconds, or 120 seconds.

[0196] The disintegrant may include, for example, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, chitosan hydrochloride, corn starch and pregelatinized starch, calcium alginate and sodium calcium alginate, sodium doxart, microcrystalline cellulose, hydroxypropyl starch, aluminum magnesium silicate, methylcellulose, sodium alginate, starch, pregelatinized starch, calcium carboxymethylcellulose, calcium glycolate cellulose, carmellose calcium, powdered cellulose, or any combination of the above.

[0197] Suitable disintegrants include crospovidone, croscarmellose sodium, sodium starch glycolate, soybean polysaccharide, cross-linked alginic acid, gellan gum, xanthan gum, calcium silicate, and cross-linked polyacrylate.

[0198] The excipient may include crospovidone, such as crospovidone CL-M, available from BASF.

[0199] A suitable crospovidone disintegrant is a 1% by weight solution in water at a temperature of 20°C to 25°C with a pH of 5 to 8 and a concentration of 0.25 g / cm³. 3 ~0.45g / cm 3It can have a bulk density and / or an average particle size of 20 μm to 40 μm.

[0200] The excipient granules may contain, for example, 1% to 40% by weight of a disintegrant such as crospovidone, 1% to 30% by weight, 1% to 25% by weight, 1% to 20% by weight, 5% to 20% by weight, 7% to 17% by weight, or 10% to 14% by weight of a disintegrant such as crospovidone, where the weight percentage is based on the total weight of the excipient granules.

[0201] The excipient granules provided by this disclosure may contain one or more additional excipients. The additional excipients may be pharmaceutically acceptable excipients.

[0202] Suitable excipients include preservatives, antioxidants, adsorbents, acidifiers, alkalizers, buffers, chelating agents, colorants, fining agents, emulsifiers, flavorings, water-soluble polymers, diluents, binders, lubricants, wetting agents, surfactants, fluidizers, and fillers.

[0203] One or more additional excipients may include diluents, binders, flavoring agents, buffers, acids, sweeteners, fillers, or any combination thereof.

[0204] The excipient granules provided by this disclosure may include, for example, 40% to 98% by weight of additional excipients or combinations of additional excipients that do not contain viscous agents and dispersants. The excipient granules provided by this disclosure may include, for example, one or more additional excipients in 40% to 98% by weight, 50% to 95% by weight, 60% to 90% by weight, 70% to 85% by weight, or 75% to 85% by weight, where the weight percentage is based on the total weight of the excipient granules.

[0205] The excipient granules provided by this disclosure may, for example, contain less than 95% by weight of an additional excipient, less than 90% by weight, less than 80% by weight, less than 70% by weight, or less than 60% by weight of one or more additional excipients, where the weight percentage is based on the total weight of the excipient granules. The excipient granules provided by this disclosure may, for example, contain more than 40% by weight of one or more additional excipients, more than 50% by weight, more than 60% by weight, more than 70% by weight, more than 80% by weight, or more than 90% by weight of one or more additional excipients, where the weight percentage is based on the total weight of the excipient granules.

[0206] The excipient granules may contain a diluent or a combination of diluents. The diluent may be a pharmaceutically acceptable diluent.

[0207] Diluents can provide bulk to excipient granules, improve flow properties, and facilitate processing.

[0208] Examples of suitable diluents include microcrystalline cellulose, powdered cellulose, anhydrous lactose, lactose monohydrate, spray-dried lactose, mannitol, starch, pregelatinized starch, corn starch, corn starch, sorbitol, sucrose, compressed sugar, powdered sugar, sugar globules, dextrate, dextrin, dextrose, dibasic calcium phosphate, anhydrous calcium phosphate, calcium carbonate, maltose, maltodextrin, kaolin, dibasic calcium phosphate, dihydrated calcium phosphate, tribasic calcium phosphate, calcium sulfate, Cerabrate, calcium lactate, cellulose acetate, silicified microcrystalline cellulose, cellulose acetate, corn syrup, pregelatinized starch and corn starch, corn syrup solids, erythritol, ethylcellulose, ethyl acrylate, and Examples include methyl methacrylate copolymer dispersions, fructose, isomalt, alpha-lactalbumin, lactitol, magnesium carbonate, magnesium oxide, methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl methacrylate copolymer, polydextrose, sodium chloride, simethicone, pregelatinized starch, pea starch, hydroxypropyl pea starch, pregelatinized hydroxypropyl pea starch, potato starch, hydroxypropyl potato starch, pregelatinized hydroxypropyl potato starch, starch, tapioca, wheat starch, hydrolyzed starch, pullulan, talc, amino methacrylate copolymer, trehalose, xylitol, and any combination of the above.

[0209] Suitable diluents include lactose, microcrystalline cellulose, starch, calcium phosphate such as anhydrous dibasic calcium phosphate, hydrated dibasic calcium phosphate, and tribasic calcium phosphate, calcium carbonate, maltodextrin, mannitol, sorbitol, and sodium chloride.

[0210] The diluent may include anhydrous dibasic calcium phosphate.

[0211] Anhydrous dibasic calcium phosphate can be A-Comprez®, available from Markan Global Enterprises.

[0212] The excipient granules may contain, for example, a diluent such as anhydrous dibasic calcium phosphate in amounts of 1% to 40% by weight, 10% to 30% by weight, 15% to 25% by weight, or 17% to 23% by weight, where the percentage by weight is based on the total weight of the excipient granules.

[0213] The excipient granules provided by this disclosure may include a binder or a combination of binders. The binder may be a pharmaceutically acceptable binder.

[0214] The binder promotes the aggregation of the components of the excipient granules.

[0215] Examples of suitable binders include natural binders such as starch, pregelatinized starch, sodium alginate, and gelatin; synthetic and semi-synthetic binders such as polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polymethacrylate, sodium carboxymethylcellulose, polyethylene glycol, and methylcellulose; sugars such as lactose, sucrose, starch, cellulose, and modified celluloses such as microcrystalline cellulose, and cellulose ethers such as hydroxypropylcellulose, as well as sugar derivatives such as sorbitol, xylitol, and mannitol.

[0216] Other suitable binders include acacia, copovidone, carbomer, corn starch and pregelatinized starch, calcium carboxymethylcellulose, calcium glycolate, carmellosum calcium, sodium carboxymethylcellulose, carmellose sodium, ceratonia, chitosan hydrochloride, dextrine, dextrin, ethylcellulose, liquid glucose, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropyl starch, hydroxypropylmethylcellulose, inulin, aluminum magnesium silicate, maltodextrin, methylcellulose, polyethylene glycol, polyethylene oxide, povidone, sodium alginate, starch, pregelatinized starch, sucrose, compressed sugar, zein, gelatin, polymethyl methacrylate, sorbitol, glucose, and sodium alginate.

[0217] Suitable binders include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol.

[0218] The binder may include polyvinylpyrrolidone.

[0219] A suitable polyvinylpyrrolidone may have an average molecular weight of, for example, 58,000 daltons, which is determined by column chromatography. A suitable polyvinylpyrrolidone may have a viscosity of, for example, 2.5 cP in a 5% aqueous solution at 25°C. A suitable polyvinylpyrrolidone may have an average particle size of, for example, 80 μm. A suitable polyvinylpyrrolidone may have a viscosity of, for example, 0.36 g / cm³. 3 bulk density and / or 0.47 g / cm³ 3 It can have a tap density of .

[0220] The excipient granules may contain, for example, a binder such as polyvinylpyrrolidone in amounts of 1% to 30% by weight, 2% to 25% by weight, 5% to 20% by weight, or 7% to 13% by weight, where the weight percentage is based on the total weight of the excipient granules.

[0221] The excipient granules provided by this disclosure may include flavoring agents or combinations of flavoring agents. The flavoring agents may be pharmaceutically acceptable flavoring agents.

[0222] Flavoring agents can improve the taste of pharmaceutical compositions and mask unpleasant tastes of active pharmaceutical ingredients. The type of unpleasant taste being masked can determine the appropriate choice of flavoring agent.

[0223] Suitable flavorings include vanillin, peppermint flavor powder, berry flavor powder, strawberry flavor powder, orange flavor powder, lemon flavor powder, orange essence, ethyl maltol, eucalyptus oil, isobutyl alcohol, sodium succinate, adipic acid, almond oil, anethole, benzaldehyde, denatonium benzoate, ethyl acetate, ethyl vanillin, ethylcellulose, fructose, fumaric acid, l-glutamate hydrochloride, lactitol, leucine, malic acid, maltol, menthol / lacementol, methionine, methyl salicylate, sodium glutamate, peppermint oil, liquid strawberry flavoring, peppermint spirit, racemethionine, rose oil, high-concentration rose water, sodium acetate, sodium lactate solution, tartaric acid, thymol, fumaric acid, inulin, isomalt, and neohesperidin dihydrochalcone.

[0224] Flavorings may include citrus fruit flavorings, berry flavorings, punch flavorings, or any combination of the above.

[0225] The excipient granules provided by this disclosure may, for example, contain 1% to 40% by weight of a flavoring agent, 5% to 35% by weight, 10% to 35% by weight, 15% to 35% by weight, 20% to 30% by weight, or 22% to 28% by weight of a flavoring agent, where the weight percentage is based on the total weight of the excipient granules.

[0226] The excipient granules provided by this disclosure may include a buffer or a combination of buffers. The buffer may be a pharmaceutically acceptable buffer.

[0227] Suitable buffering agents include sodium citrate dihydrate, anhydrous citrate, dibasic sodium phosphate and monobasic sodium phosphate, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, and anhydrous sodium citrate.

[0228] The buffering agent may include sodium citrate dihydrate.

[0229] The excipient granules may contain, for example, 0.1% to 10% by weight of a buffering agent, 0.5% to 8% by weight, 0.5% to 6.5% by weight, 1% to 5% by weight, or 2% to 4% by weight of a buffering agent such as sodium citrate dihydrate, where the weight percentage is based on the total weight of the excipient granules.

[0230] The excipient granules provided by this disclosure may contain an acidifying agent or a combination of acidifying agents. The acidifying agent may be a pharmaceutically acceptable acidifying agent.

[0231] Suitable acidifying agents include anhydrous sodium citrate, fumaric acid, hydrochloric acid, and nitric acid.

[0232] The excipient granules may contain, for example, 0.1% to 10% by weight of an acid, 0.5% to 8% by weight, 1% to 7% by weight, 2% to 6% by weight, or 3% to 5% by weight of anhydrous sodium citrate, where the percentage by weight is based on the total weight of the excipient granules.

[0233] The excipient granules provided by this disclosure may include a sweetener or a combination of sweeteners. The sweetener may include pharmaceutically acceptable sweeteners.

[0234] Suitable sweeteners include sucralose, sodium saccharin, neotame, sucrose, acesulfame potassium, aspartame, aspartame acesulfame, corn syrup, corn syrup solids, dextrose, dextrose excipients, erythritol, fructose, galactose, glucose, glycerin, inulin, invert sugar, isomalt, lactitol, maltitol, maltose, mannitol, saccharin, calcium saccharin, sorbitol, starch hydrolysates, hydrogenated sugars, compressed sugars, powdered sugar, tagatose, trehalose, and xylitol.

[0235] Suitable sweeteners include mannitol, sucralose, aspartame, dextrose, glycerin, sodium saccharin, sorbitol, and sucrose.

[0236] The sweetener may include sucralose.

[0237] The excipient granules may contain, for example, 0.1% to 10% by weight of a sweetener such as sucralose, 0.1% to 7% by weight, 0.1% to 6% by weight, 1% to 5% by weight, or 2% to 4% by weight of a sweetener such as sucralose, where the weight percentage is based on the total weight of the excipient granules.

[0238] The excipient granules provided by this disclosure may include fillers or combinations of fillers. The fillers may be pharmaceutically acceptable fillers.

[0239] Examples of suitable fillers include starch 1500, gelatinized starch 1500, microcrystalline cellulose, calcium phosphate powder, dicalcium phosphate dihydrate, mannitol, or dicalcium phosphate powder, lactose, calcium carbonate, calcium sulfate, compressed sugar, dextrate, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, powdered cellulose, sucrose, and any combination of the above.

[0240] The filler may include microcrystalline cellulose such as Avicel® PH-101 or Celphere® CP-305, which are available from Asahi-Kasei.

[0241] The excipient granules provided by this disclosure may include, for example, 1% to 20% by weight of a filler such as microcrystalline cellulose, 5% to 15% by weight, or 7% to 13% by weight of a filler such as microcrystalline cellulose, where the weight percentage is based on the total weight of the excipient granules.

[0242] The excipient granules provided by this disclosure may include, for example, a viscous agent, a disintegrant, and one or more additional excipients, the one or more additional excipients may include a filler or a combination of fillers. The excipient granules may include, for example, 40% to 98% by weight of filler, 50% to 90% by weight, or 60% to 80% by weight of filler, where the weight percentage is based on the total weight of the excipient granules. The excipient granules may include, for example, less than 90% by weight of filler, less than 80% by weight, less than 70% by weight, less than 60% by weight, or less than 50% by weight of filler, where the weight percentage is based on the total weight of the excipient granules. The excipient granules may include, for example, more than 40% by weight of filler, more than 50% by weight, more than 60% by weight, more than 70% by weight, more than 80% by weight, or more than 90% by weight of filler, where the weight percentage is based on the total weight of the excipient granules.

[0243] The excipient granules provided by this disclosure may include pharmaceutically acceptable fluidizers or combinations of pharmaceutically acceptable fluidizers. Examples of suitable pharmaceutically acceptable fluidizers include magnesium stearate, magnesium silicate, calcium stearate, sodium lauryl sulfate, sodium stearyl fumarate, magnesium lauryl sulfate, stearic acid, calcium stearate, glyceryl behenate, behenoyl polyoxylglyceride, glyceryl dibehenate, lauric acid, glyceryl monostearate, glyceryl tristearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, and polysol Examples include polysorbate 20, polyoxyl 10 oleyl ether, polyoxyl 15 hydroxystearate, polysorbate 40, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 60, polysorbate 80, potassium benzoate, sodium benzoate, sorbitan monolaurate, sorbitan monooleate, sodium stearate, sorbitan monopalmitate, sorbitan monostearate, zinc stearate, sorbitan sesquioleate, sorbitan trioleate, and talc.

[0244] The excipient granules provided by this disclosure may include pharmaceutically acceptable lubricants or combinations of pharmaceutically acceptable lubricants. Examples of suitable pharmaceutically acceptable lubricants include colloidal silicon dioxide, talc, tribasic calcium phosphate, calcium silicate, powdered cellulose, magnesium oxide, sodium stearate, magnesium silicate, silica, dental type, magnesium trisilicate, and hydrophobic colloidal silica.

[0245] The excipient granules provided by this disclosure may include a pharmaceutically acceptable alkalizing agent or a combination of pharmaceutically acceptable alkalizing agents. Examples of suitable pharmaceutically acceptable alkalizing agents include ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, and trolamine.

[0246] The excipient granules provided by this disclosure may include pharmaceutically acceptable surfactants or combinations of pharmaceutically acceptable surfactants. Examples of suitable pharmaceutically acceptable surfactants include behenoyl polyoxylglycerides, polysorbate 20, polysorbate 40, sodium doxate, polysorbate 60, polysorbate 80, benzalkonium chloride, caprylocaproyl polyoxylglycerides, cetylpyridinium chloride, lauroyl polyoxylglycerides, linoleoyl polyoxylglycerides, octoxynol 9, oleoyl polyoxylglycerides, poloxamer, polyoxyl 10 oleyl ether, and polyoxyl 15 hydr Examples include oxystearate, non-oxynol 9, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, pullulan, polyoxyl lauryl ether, polyoxyl stearyl ether, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, polyoxystearate, sorbitan monopalmitate, sorbitan monostearate, stearoyl polyoxylglyceride, sorbitan sesquioleate, sorbitan trioleate, and tyroxapol.

[0247] The excipient granules provided by this disclosure may include pharmaceutically acceptable colorants or combinations of pharmaceutically acceptable colorants. Examples of suitable pharmaceutically acceptable colorants include caramel, iron oxide, titanium dioxide, iron oxide, aluminum oxide, FD&C Red 40 / Allura Red AC, amaranth, FD&C Blue 1 / Brilliant Blue FCF, canthaxanthin, carmine, carmoisine (azorvin), curcumin (turmeric), FD&C Red 3 / erythrosine, Fast Green FCF, Green S (Lisamin Green), and D&C Red 30 / Herendon. Examples include pink, FD&C Blue 2 / Indigo Carmine, black iron oxide, red iron oxide, D&C Red 7 / Lysol Rubin BK, Patent Blue V, D&C Red 28 / Phloxine B, yellow iron oxide, D&C Red 27 / Phloxine O, Ponceau 4R (Cochineal Red A), Quinoline Yellow WS, D&C Yellow 10, Riboflavin (Lactoflavin), FD&C Yellow 5 / Tartrazine, and FD&C Yellow 6 / Sunset Yellow FCF.

[0248] The excipient granules and excipient granules provided by this disclosure may, for example, contain 2% to 22% by weight of a binder, 10% to 30% by weight of a diluent, 1% to 20% by weight of a filler, 15% to 35% by weight of a flavoring agent, 0.5% to 6.5% by weight of a buffering agent, 0.5% to 8% by weight of an acidifying agent, and / or 0.1% to 6% by weight of a sweetener, where the percentage by weight is based on the total weight of the excipient granules or excipient granules.

[0249] The excipient granules and excipient granules provided by this disclosure may, for example, contain 1% to 35% by weight of a viscous agent and 1% to 25% by weight of a disintegrant, where the percentage by weight is based on the total weight of the excipient granules or excipient granules.

[0250] The excipient granules and excipient granules provided by this disclosure may, for example, contain 5% to 15% by weight of a binder, 17% to 27% by weight of a diluent, 6% to 16% by weight of a filler, 20% to 30% by weight of a flavoring agent, 1% to 5% by weight of a buffering agent, 2% to 6% by weight of an acidifying agent, and / or 1% to 5% by weight of a sweetener, where the percentage by weight is based on the total weight of the excipient granules or excipient granules.

[0251] The excipient granules and excipient granules provided by this disclosure may, for example, contain 5% to 15% by weight of a viscous agent and 7% to 17% by weight of a disintegrant, where the weight percentage is based on the total weight of the excipient granules or excipient granules.

[0252] In the excipient granules and excipient granules provided by this disclosure, the viscous agent may include xanthan gum, the disintegrant may include crospovidone, the binder may include polyvinylpyrrolidone, the diluent may include dicalcium phosphate, the filler may include microcrystalline cellulose, the flavoring agent may include berry / punch flavoring agents, the buffering agent may include sodium citrate dihydrate, the acidifying agent may include anhydrous citrate, and / or the sweetener may include sucralose, and the weight % is based on the total weight of the excipient granules or excipient granules.

[0253] The excipient granules provided by this disclosure may have, for example, average granule sizes of 100 μm to 600 μm, 200 μm to 600 μm, 100 μm to 550 μm, 100 μm to 500 μm, 200 μm to 500 μm, or 250 μm to 450 μm, the average granule size of which is determined by sieve analysis or laser diffraction.

[0254] The excipient granules may have a particle size distribution characterized by, for example, 8.5% by weight of mesh size greater than 35 (500 μm), 39% by weight of mesh size between 35 and 60 (500 and 250 μm), 52.2% of pan, and 52.2% by weight of mesh size less than 35 (500 μm), and the particle size is determined by sieve analysis or laser diffraction.

[0255] The excipient granules (35-60 mesh fraction) can have an average bulk density of, for example, 0.5 g / mL to 0.9 g / mL, and the bulk density is determined using a bulk density cylinder.

[0256] The excipient granules provided by this disclosure may have bulk densities of, for example, 0.5 g / mL to 0.7 g / mL, 0.6 g / mL to 0.9 g / mL, 0.65 g / mL to 0.85 g / mL, or 0.7 g / mL to 0.8 g / mL, and the bulk density is as specified in the USP <616> , determined according to Method 1.

[0257] The excipient granules provided by this disclosure may have, for example, an average tap density of 500 g / mL to 900 g / mL, 550 g / mL to 850 g / mL, 600 g / mL to 800 g / mL, or 650 g / mL to 750 g / mL, where the average tap density is as per USP <616> It is determined according to the following.

[0258] Excipient granules provided by this disclosure may have Hausner ratios of, for example, 1.0–1.5, 1.1–1.4, 1.1–1.35, or 1.1–1.25, and pharmaceutical granules may have equivalent Hausner ratios, and the average Hausner ratio is the USP <1174> It is determined according to the following.

[0259] The excipient granules provided by this disclosure may have, for example, a compressibility index of 8 to 22, 10 to 20, or 12 to 18.

[0260] The excipient granules provided by this disclosure may have, for example, a Flodex value of less than 5 mm, less than 4 mm, less than 3 mm, or less than 2 mm, and the Flodex value is a USP <1174> It is determined according to the following.

[0261] The excipient granules provided by this disclosure may have, for example, a degree of abrasion of less than 2 or less than 1, the degree of abrasion of which is determined using an ultrasonic sieve.

[0262] The excipient granules provided by this disclosure may have a drying loss of 1% to 4% by weight, such as 1.5% to 3.5% by weight, or 2% to 3% by weight, the drying loss being determined by thermogravimetric analysis.

[0263] The excipient granules provided by this disclosure can be completely dissolved in an aqueous solution at a temperature of 20°C to 25°C in, for example, less than 120 seconds, less than 90 seconds, less than 60 seconds, or less than 30 seconds, where complete dissolution is defined as the time from when the excipient granules are combined with the aqueous solution until the viscosity of the viscous solution exceeds 90% of its maximum viscosity.

[0264] A solution prepared by combining 1% to 5% by weight of excipient granules with 95% to 99% by weight of water at a temperature of 20°C to 25°C can achieve its maximum viscosity within 15 to 120 seconds, for example, 15 to 60 seconds after mixing, where the weight percentage is based on the total weight of the excipient granules and water. Mixing can be achieved, for example, by stirring, agitating, and / or vortex mixing the excipient granules in water or a non-viscous aqueous solution.

[0265] A solution prepared by combining 1% to 5% by weight of excipient granules with 95% to 99% by weight of water at a temperature of 20°C to 25°C, such as 23°C, can provide a solution having a viscosity of, for example, 25 cp to 200 cp.

[0266] The excipient granules provided by this disclosure can be completely dissolved in less than 60 seconds or less than 30 seconds when prepared as a 1 w / v% solution in water at a temperature of 20°C to 25°C, such as 23°C.

[0267] When the excipient granules provided by this disclosure are re-prepared as a 1 w / v% solution in water at a temperature of 20°C to 25°C, such as 23°C, they can provide a solution having a pH of 4.0 to 7.0, or 4.0 to 8.0, such as 4.0 to 5.0.

[0268] When 1.2 g of the excipient granules provided by this disclosure are re-prepared in 40 mL of water at a temperature of 20°C to 25°C, such as 23°C, the resulting solution exhibits a viscosity-time profile as shown in Figure 5.

[0269] When 1.2 g of the excipient granules provided by this disclosure are re-prepared in 40 mL of water at a temperature of 20°C to 25°C, such as 23°C, the resulting solution exhibits a brightness-to-time profile as shown in Figure 6.

[0270] The excipient granules can be configured to provide a viscosity of 20 cP to 100 cP when 1.2 gm of excipient granules is mixed with 40 mL of water at a temperature of 20°C to 25°C, such as 23°C.

[0271] After mixing 1.2 g of a solution of the excipient granules provided in this disclosure with 40 mL of water for 90 seconds at a temperature of 20°C to 25°C, such as 23°C, the solution may have a viscosity in the range of 45 cP to 80 cP.

[0272] After mixing 1.2 g of a solution of the excipient granules provided in this disclosure with 40 mL of water for 60 seconds at a temperature of 20°C to 25°C, such as 23°C, the solution may have a viscosity in the range of 35 cP to 60 cP.

[0273] After mixing 1.2 g of a solution of the excipient granules provided in this disclosure with 40 mL of water for 30 seconds at a temperature of 20°C to 25°C, such as 23°C, the solution may have a viscosity in the range of 15 cP to 40 cP.

[0274] The excipient granules provided by this disclosure can provide a solution having a re-adjusted pH of 4 to 6.

[0275] The physical properties of excipient granules can be selected to minimize or prevent sedimentation or separation of the pharmaceutical composition containing the excipient granules and pharmaceutical granules. To promote the ability of pharmaceutical granules to disperse homogeneously in viscous solutions prepared using excipient granules, it may be desirable that the pharmaceutical composition containing the excipient granules and pharmaceutical granules is homogeneously dispersed and remains homogeneously dispersed during storage and transport. Homogeneous dispersion of excipient granules and pharmaceutical granules in a pharmaceutical composition can be promoted by the excipient granules and pharmaceutical granules having similar physical properties. For example, it may be desirable that the excipient granules and pharmaceutical granules have similar certain physical properties such as average particle size, bulk density, tap density, Hausner ratio, compressibility index, Flodex value, and / or abrasion value. For example, it may be desirable that the physical properties of the excipient granules be within + / -20%, + / -15%, + / -10%, + / -5%, or less than + / -2% of the corresponding properties of the pharmaceutical granules.

[0276] For pharmaceutical granules that include a group of one or more granules, such as immediate-release pharmaceutical granules and controlled-release pharmaceutical granules, it may be desirable that the physical property values ​​of the excipient granules be within + / -20%, + / -15%, + / -10%, + / -5%, or less than + / -2% of the corresponding property values ​​of the immediate-release pharmaceutical granules and controlled-release granules, respectively.

[0277] In the pharmaceutical compositions provided by this disclosure, the excipient granules provided by this disclosure may have an average granule size of, for example, within + / -20% of the average particle size of the pharmaceutical granules combined with the excipient granules, within + / -15%, within + / -10%, or within + / -5% of the average particle size of the pharmaceutical granules combined with the excipient granules.

[0278] In the pharmaceutical compositions provided by this disclosure, the excipient granules provided by this disclosure may have an average bulk density of, for example, within + / -20% of the average bulk density of the pharmaceutical granules combined with the excipient granules, within + / -15%, within + / -10%, within + / -5%, or less than + / -2% of the average bulk density of the pharmaceutical granules combined with the excipient granules.

[0279] In the pharmaceutical compositions provided by this disclosure, the excipient granules provided by this disclosure may have an average tap density of, for example, within + / -20% of the average tap density of the pharmaceutical granules combined with the excipient granules, within + / -15%, within + / -10%, within + / -5%, or less than + / -2% of the average tap density of the pharmaceutical granules combined with the excipient granules.

[0280] In the pharmaceutical compositions provided by this disclosure, the excipient granules provided by this disclosure may have a Hausner ratio such that, for example, it is within + / -20% of the average Hausner ratio of the pharmaceutical granules combined with the excipient granules, within + / -15%, within + / -10%, within + / -5%, or less than + / -2% of the Hausner ratio of the drug-containing granules combined with the excipient granules.

[0281] In the pharmaceutical compositions provided by this disclosure, the excipient granules provided by this disclosure may have a compressibility index of, for example, within + / -20% of the compressibility index of the pharmaceutical granules combined with the excipient granules, within + / -15%, within + / -10%, within + / -5%, or less than + / -2% of the compressibility index of the pharmaceutical granules combined with the excipient granules.

[0282] In the pharmaceutical composition provided by the present disclosure, the excipient granulate provided by the present disclosure can have a Flodex value, for example, within + / - 20%, within + / - 15%, within + / - 10%, or within + / - 5%, or less than + / - 5% of the Flodex value of the pharmaceutical granulate combined with the excipient granulate.

[0283] In the pharmaceutical composition provided by the present disclosure, the excipient granulate provided by the present disclosure can have a wear degree, for example, within + / - 20%, within + / - 15%, within + / - 10%, or within + / - 5%, or less than + / - 2% of the wear degree of the pharmaceutical granulate combined with the excipient granulate.

[0284] The pharmaceutical composition provided by the present disclosure can include an immediate-release pharmaceutical granulate and a modified-release pharmaceutical granulate.

[0285] The pharmaceutical composition can include, for example, 20 wt% to 30 wt% of an immediate-release pharmaceutical granulate, 22 wt% to 28 wt% or 24 wt% to 26 wt% of an immediate-release pharmaceutical granulate, where wt% is based on the total weight of the pharmaceutical composition.

[0286] The pharmaceutical composition can include, for example, 62 wt% to 72 wt% of an immediate-release pharmaceutical granulate, 64 wt% to 70 wt% or 66 wt% to 68 wt% of an immediate-release pharmaceutical granulate, where wt% is based on the total weight of the pharmaceutical composition.

[0287] The pharmaceutical composition can include, for example, 2 wt% to 12 wt% of an excipient granulate, 4 wt% to 10 wt% or 6 wt% to 8 wt% of an excipient granulate, where wt% is based on the total weight of the pharmaceutical composition.

[0288] The pharmaceutical composition may include, for example, 2.5% to 12.5% ​​by weight of excipient granules, 3.5% to 11.5% by weight, 4.5% to 10.5% by weight, 5.5% to 9.5% by weight, 6.5% to 8.5% by weight, 7.0% to 8.0% by weight, or 7.5% by weight, where the weight percentage is based on the total weight of the pharmaceutical composition.

[0289] The pharmaceutical composition may include, for example, 20% to 30% by weight of immediate-release pharmaceutical granules, 62% to 72% by weight of controlled-release pharmaceutical granules, and 2% to 12% by weight of excipient granules, where the weight percentages are based on the total weight of the pharmaceutical composition.

[0290] The pharmaceutical composition may include, for example, 22% to 28% by weight of immediate-release pharmaceutical granules, 64% to 72% by weight of controlled-release pharmaceutical granules, and 4% to 10% by weight of excipient granules, where the weight percentages are based on the total weight of the pharmaceutical composition.

[0291] The pharmaceutical composition may include, for example, 24% to 26% by weight of immediate-release pharmaceutical granules, 66% to 70% by weight of controlled-release pharmaceutical granules, and 6% to 9% by weight of excipient granules, where the weight percentages are based on the total weight of the pharmaceutical composition.

[0292] The pharmaceutical composition may, for example, contain 24% to 38% by weight of 4-((L-valyl)oxy)butanoic acid in an immediate-release component and 62% to 76% by weight of 4-((L-valyl)oxy)butanoic acid in a controlled-release component, where the weight percentage is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0293] The pharmaceutical composition may, for example, contain 26% to 36% by weight of 4-((L-valyl)oxy)butanoic acid in an immediate-release component and 64% to 74% by weight of 4-((L-valyl)oxy)butanoic acid in a controlled-release component, where the weight percentage is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0294] The pharmaceutical composition may, for example, contain 28% to 34% by weight of 4-((L-valyl)oxy)butanoic acid in an immediate-release component and 66% to 72% by weight of 4-((L-valyl)oxy)butanoic acid in a controlled-release component, where the weight percentage is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0295] The pharmaceutical composition may, for example, contain 30% to 32% by weight of 4-((L-valyl)oxy)butanoic acid in an immediate-release component and 68% to 70% by weight of 4-((L-valyl)oxy)butanoic acid in a controlled-release component, where the weight percentage is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0296] In a pharmaceutical composition, the ratio of the weight of 4-((L-valyl)oxy)butanoic acid in the adjusted-release pharmaceutical granules to the weight of 4-((L-valyl)oxy)butanoic acid in the immediate-release pharmaceutical granules can be, for example, 1.7 to 3.7, 1.9 to 3.5, 2.1 to 3.3, 2.3 to 3.1, or 2.5 to 2.9.

[0297] In the pharmaceutical composition, the adjusted-release pharmaceutical granules may contain, for example, 64% to 74% by weight of 4-((L-valyl)oxy)butanoic acid, and the immediate-release pharmaceutical granules may contain 26% to 36% by weight of 4-((L-valyl)oxy)butanoic acid, where the weight percentage is based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0298] The pharmaceutical composition may, for example, be in powder form and may further contain one or more additional excipients independent of the excipient granules. The one or more additional excipients may include pharmaceutically acceptable excipients.

[0299] One or more additional excipients can promote the dispersion of the excipient granules and / or minimize or prevent aggregation of the excipient granules and / or the pharmaceutical granules.

[0300] One or more additional excipients can include, for example, an antistatic agent.

[0301] Examples of suitable antistatic agents include talc (hydrous magnesium silicate), magnesium stearate, and silicon dioxide.

[0302] The pharmaceutical composition can include hydrous magnesium silicate (talc).

[0303] The pharmaceutical composition can include, for example, an antistatic agent such as hydrous magnesium silicate in an amount of 0.1 wt% to 1.2 wt%, 0.2 wt% to 1.1 wt%, 0.3 wt% to 1.0 wt%, or 0.4 wt% to 0.9 wt%, where wt% is based on the total weight of the pharmaceutical composition.

[0304] The pharmaceutical composition and oral pharmaceutical composition provided by the present disclosure can include a therapeutically effective dose of 4-((L-valyl)oxy)butanoic acid.

[0305] For a 14.5 g dose of 4-((L-valyl)oxy)butanoic acid, 10 g of 4-((L-valyl)oxy)butanoic acid can be in the modified release pharmaceutical granules, and 4.5 g of 4-((L-valyl)oxy)butanoic acid can be in the immediate release pharmaceutical granules.

[0306] For a 14.5 g dose of 4-((L-valyl)oxy)butanoic acid, 8 g to 12 g of 4-((L-valyl)oxy)butanoic acid can be in the modified release pharmaceutical granules, and 2.5 g to 6.5 g of 4-((L-valyl)oxy)butanoic acid can be in the immediate release pharmaceutical granules.

[0307] A 14.5 g dose of 4-((L-valyl)oxy)butanoic acid can include 13.34 g of modified release pharmaceutical granules, 5 g of immediate release pharmaceutical granules, 1.50 g of excipient granules, and an antistatic agent such as 0.10 g of talc. <0​​A 14.5g dose of 4-((L-valyl)oxy)butanoic acid may contain 11.34g to 15.35g of controlled-release pharmaceutical granules, 3g to 7g of immediate-release pharmaceutical granules, 1g to 2g of excipient granules, and 0.05g to 0.15g of an antistatic agent such as talc.

[0309] The dosage of 4-((L-valyl)oxy)butanoic acid may include, for example, 1g to 30g of 4-((L-valyl)oxy)butanoic acid in amounts such as 2g to 25g, 4g to 20g, 5g to 20g, or 10g to 15g of 4-((L-valyl)oxy)butanoic acid.

[0310] A pharmaceutical composition may contain a unit dose of 4-((L-valyl)oxy)butanoic acid, where unit dose refers to a single dose capable of treating a disease or symptoms of a disease.

[0311] The oral pharmaceutical compositions provided by this disclosure may include a viscous aqueous solution and an active pharmaceutical component. The oral pharmaceutical compositions can be formed by combining the pharmaceutical composition with an aqueous solution such as water. Oral pharmaceutical compositions that can be taken orally by a patient.

[0312] The oral pharmaceutical compositions provided by this disclosure may include oral pharmaceutical compositions for oral administration prepared by mixing the pharmaceutical compositions provided by this disclosure with water or an aqueous solution to provide a viscous solution containing the adjusted-release pharmaceutical granules provided by this disclosure dispersed and suspended in a viscous solution. The viscous solution may contain components of excipient granules dissolved in water or an aqueous solution. The viscous solution may also contain 4-((L-valyl)oxy)butanoic acid dissolved in the viscous solution, the 4-((L-valyl)oxy)butanoic acid contained therein is provided by partially or completely dissolved immediate-release pharmaceutical granules. The viscous solution may further contain partially dissolved immediate-release pharmaceutical granules suspended and dispersed in the viscous solution.

[0313] The oral pharmaceutical compositions provided herein may include viscous aqueous solutions. The oral pharmaceutical compositions are intended for oral administration.

[0314] A viscous aqueous solution can be prepared by mixing the excipient granules provided by this disclosure with an aqueous solution.

[0315] When excipient granules are mixed with water, the contents of the excipient granules provide concentrations of excipient granules such as 0.005 g / mL to 0.060 g / mL, 0.010 g / mL to 0.055 g / mL, 0.015 g / mL to 0.050 g / mL, 0.015 g / mL to 0.045 g / mL, 0.02 g / mL to 0.04 g / mL, or 0.025 g / mL to 0.035 g / mL, where g / mL is based on the grams of excipient granules mixed with a certain volume of water.

[0316] For example, an oral pharmaceutical composition can be prepared by mixing 0.2g to 2.2g (e.g., 0.4g to 2.0g, 0.6g to 1.8g, 0.8g to 1.6g, 1.0g to 1.4g) of excipient granules in 40mL of water.

[0317] The oral pharmaceutical compositions provided by this disclosure can be prepared by combining excipient granules and pharmaceutical granules with water. The excipient granules and pharmaceutical granules can be combined with water either simultaneously or sequentially. For example, the excipient granules can be combined with water first to form a viscous solution, and then the pharmaceutical granules can be combined with the viscous solution and mixed. Alternatively, the pharmaceutical granules can be combined with water first, and then the excipient granules can be added to the aqueous solution. As another example, each of the excipient granules, immediate-release pharmaceutical granules, and controlled-release pharmaceutical granules can be added to an aqueous solution such as water in any order, simultaneously, or independently, to provide an oral pharmaceutical composition.

[0318] The oral pharmaceutical composition may include a viscous solution and 4-((L-valyl)oxy)butanoic acid dissolved in the viscous solution, and / or pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid suspended in the viscous solution.

[0319] Oral pharmaceutical compositions may contain immediate-release components and controlled-release components. Immediate-release components may include 4-((L-valyl)oxy)butanoic acid dissolved in a viscous aqueous solution, immediate-release pharmaceutical granules suspended in a viscous solution, or a combination thereof. Controlled-release components may include controlled-release pharmaceutical granules suspended in a viscous solution.

[0320] The immediate-release and controlled-release components may include 4-((L-valyl)oxy)butanoic acid.

[0321] Oral pharmaceutical compositions should be stored at a temperature of 20°C to 25°C, such as 23°C, according to USP standards. <912> The viscosity can be, for example, 50 cP to 1,100 cP or 50 cP to 600 cP, determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. The oral pharmaceutical composition can be prepared at a temperature of 20°C to 25°C, such as 23°C, according to USP <912> The viscosity can be, for example, greater than 50 cP, greater than 100 cP, greater than 200 cP, greater than 400 cP, greater than 800 cP, or greater than 800 cP, as determined using a No. 62 spindle at a speed of 12 rpm according to Method 1c. The oral pharmaceutical composition can be prepared at a temperature of 20°C to 25°C, such as 23°C, according to USP <912> The viscosity can be less than 1,000 cP, less than 800 cP, less than 600 cP, less than 400 cP, less than 200 cP, or less than 100 cP, as determined using a spindle No. 62 at a speed of 12 rpm according to method 1c.

[0322] The oral pharmaceutical compositions provided by this disclosure may have viscosities of, for example, 350 cP to 550 cP after 30 seconds, 775 cP to 975 cP after 60 seconds, and 950 cP to 1150 cP after mixing with water, and the viscosity was measured at a temperature of 23°C and a concentration of 40 g / L using a No. 62 spindle at a speed of 12 rpm, USP <912> Determined according to Method 1c.

[0323] The oral pharmaceutical compositions provided by this disclosure may have a viscosity of, for example, 400 cP to 500 cP after 30 seconds, 825 cP to 925 cP after 60 seconds, and 1,000 cP to 1,100 cP after mixing with water, and the viscosity was measured at a temperature of 23°C and a concentration of 40 g / L using a No. 62 spindle at a speed of 12 rpm, USP <912> Determined according to Method 1c.

[0324] Oral pharmaceutical compositions may have a viscosity of, for example, 10 cP to 1,000 cP or 20 cP to 800 cP at a temperature of 20°C to 25°C, such as 23°C. Oral pharmaceutical compositions may have a viscosity of, for example, greater than 10 cP, greater than 20 cP, greater than 50 cP, greater than 100 cP, greater than 200 cP, greater than 400 cP, greater than 600 cP, or greater than 800 cP at a temperature of 20°C to 25°C, such as 23°C. Oral pharmaceutical compositions may have a viscosity of, for example, less than 1,000 cP, less than 800 cP, less than 600 cP, less than 400 cP, or less than 200 cP at a temperature of 20°C to 25°C, such as 23°C. Viscosity is determined using a Brookfield Model LVDV-I+ digital viscometer equipped with a Brookfield SC4-18 spindle at a spindle speed of 30 rpm. Oral pharmaceutical compositions can be prepared, for example, by mixing 10g to 20g of the pharmaceutical composition with 30mL to 50mL of water. Oral pharmaceutical compositions can be prepared, for example, by mixing 12g to 18g of the pharmaceutical composition with 35mL to 45mL of water. Oral compositions can have concentrations of 0.20g / mL to 0.70g / mL, such as 0.30g / mL to 0.42g / mL or 0.32g / mL to 0.40g / mL.

[0325] After re-preparation in water, the oral pharmaceutical composition can be injectable and have a viscosity similar to that of drinkable yogurt.

[0326] The pharmaceutical composition may include excipient granules and pharmaceutical granules containing immediate-release pharmaceutical granules and controlled-release pharmaceutical granules. When combined with a suitable amount of water, the excipient granules disintegrate, increasing the viscosity of the solution, the immediate-release pharmaceutical granules dissolve to provide an active pharmaceutical component dissolved in a viscous solution, and the controlled-release pharmaceutical granules can be suspended and dispersed in the viscous solution.

[0327] The controlled-release pharmaceutical granules can be configured to maintain the physical integrity of the controlled-release granules and to dissolve and / or release 4-((L-valyl)oxy)butanoic acid over time in the gastrointestinal tract, having a release profile determined by the components and coating of the controlled-release pharmaceutical granules or combination of controlled-release pharmaceutical granules.

[0328] A pharmaceutical composition comprising approximately 7.6% by weight of excipient granules, approximately 25.2% by weight of immediate-release pharmaceutical granules, and approximately 67.2% by weight of controlled-release pharmaceutical granules may exhibit a dissolution profile as shown in Figure 10A, the dissolution profile of which is determined as described in Example 6.

[0329] A pharmaceutical composition comprising approximately 7.6% by weight of excipient granules, approximately 25.2% by weight of immediate-release pharmaceutical granules, and approximately 67.2% by weight of controlled-release pharmaceutical granules can exhibit a 4-((L-valyl)oxy)butanoic acid solubility profile in which 26% to 46% are released within 0.5 hours, 41% to 61% are released within 1 hour, 63% to 83% are released within 2 hours, and 73% to 93% are released within 4 hours, and the solubility profile is determined as described in Example 6.

[0330] A pharmaceutical composition comprising approximately 7.6% by weight of excipient granules, approximately 25.2% by weight of immediate-release pharmaceutical granules, and approximately 67.2% by weight of controlled-release pharmaceutical granules can exhibit a 4-((L-valyl)oxy)butanoic acid solubility profile in which 31% to 41% are released within 0.5 hours, 46% to 56% are released within 1 hour, 68% to 78% are released within 2 hours, and 78% to 88% are released within 4 hours, and the solubility profile is determined as described in Example 6.

[0331] After storing the pharmaceutical compositions provided by this disclosure in a high-barrier pouch at 5±3°C or 25±2°C / 60±5%RH for 18 months, the 4-((L-valyl)oxy)butanoic acid solubility profile is the same as that of the 4-((L-valyl)oxy)butanoic acid solubility profile before storage.

[0332] The pharmaceutical composition provided by this disclosure is sealed in a high-barrier pouch and stored at 5±3°C or 25±2°C / 60±5%RH for 18 months, after which the re-preparation time is approximately 15 seconds.

[0333] After storing the pharmaceutical composition provided by this disclosure in a high-barrier pouch at 5±3°C or 25±2°C / 60±5%RH for 18 months, the 4-((L-valyl)oxy)butanoic acid content is more than 96% of the 4-((L-valyl)oxy)butanoic acid content before storage.

[0334] The pharmaceutical compositions provided by this disclosure may have an initial total impurity content of 0.2% or less and an L-valine impurity content of less than 0.2%.

[0335] After storing the pharmaceutical composition provided by this disclosure in a sealed high-barrier pouch at 5±3°C for 18 months, the total impurity content is 0.3% or less, and after storing it in a sealed high-barrier pouch at 25±2°C / 60±5%RH for 18 months, the total impurity content is 0.6% or less.

[0336] After storing the pharmaceutical composition provided by this disclosure in a sealed high-barrier pouch at 5±3°C for 18 months, the L-valine impurity content is 0.3% or less, and after storing it in a sealed high-barrier pouch at 25±2°C / 60±5%RH for 18 months, the L-valine impurity content is 0.4% or less.

[0337] The methods provided by this disclosure may include combining excipient granules, immediate-release pharmaceutical granules, and adjusted-release pharmaceutical granules with water to provide an oral pharmaceutical composition in the form of a viscous solution containing adjusted-release pharmaceutical granules.

[0338] The methods provided by this disclosure may include the user opening a package containing the excipient granules provided by this disclosure, pouring the excipient granules into an aqueous solution, and mixing the excipient granules in the aqueous solution to provide a viscous solution.

[0339] The methods provided by this disclosure may include the user opening a package containing the excipient granules and pharmaceutical granules provided by this disclosure, placing the excipient granules and pharmaceutical granules in an aqueous solution, mixing the excipient granules and pharmaceutical granules in the aqueous solution, thereby providing a viscous aqueous solution containing 4-((L-valyl)oxy)butanoic acid dissolved in a viscous solution and / or immediate-release granules, and adjusted-release pharmaceutical granules suspended in the viscous aqueous solution.

[0340] When combined with a suitable amount of water, the pharmaceutical compositions provided by this disclosure are configured to provide a solution having a viscosity capable of suspending pharmaceutical granules. The suspension may include pharmaceutical granules suspended in a viscous solution.

[0341] The aqueous solution may have a volume of, for example, 25 mL to 250 mL, 25 mL to 200 mL, 25 mL to 150 mL, 25 mL to 100 mL, or 25 mL to 75 mL.

[0342] The aqueous solution may contain water such as tap water.

[0343] The pharmaceutical compositions provided by this disclosure may be included in a kit that can be used to administer 4-((L-valyl)oxy)butanoic acid to a patient for therapeutic purposes. The kit may include the pharmaceutical composition, instructions for preparing an oral pharmaceutical composition suitable for oral administration to a patient, and instructions for administering the oral pharmaceutical composition to a patient. The kit may include the pharmaceutical composition provided by this disclosure, instructions for combining the contents of the kit with an aqueous solution to provide an oral pharmaceutical composition, and instructions for administering the oral pharmaceutical composition to a patient.

[0344] The kit may include a primary package and a secondary package containing the pharmaceutical composition.

[0345] Pharmaceutical compositions or granules may be included in primary packaging such as containers, sachets, blister packs, packages, or dispensers, along with instructions for the preparation and administration of oral pharmaceutical compositions.

[0346] The user instructions provided with the kit may be printed and / or supplied, for example, on electronically readable media, videocassettes, audiotapes, or flash memory devices, or made public on an internet website, or distributed to patients and / or healthcare providers as electronic communications.

[0347] Pharmaceutical granules containing immediate-release granules and controlled-release granules, as well as pharmaceutical compositions containing excipient granules, immediate-release granules, and controlled-release granules, can exhibit a solubility profile of 4-((L-valyl)oxy)butanoic acid, as substantially shown in Figure 3. The components and solubility conditions of the pharmaceutical compositions are provided in Example 2.

[0348] Pharmaceutical granules containing immediate-release granules and controlled-release granules, as well as pharmaceutical compositions containing excipient granules, immediate-release granules, and controlled-release granules, can exhibit a dissolution profile in which 40% to 60% of 4-((L-valyl)oxy)butanoic acid is released into the dissolving solvent within 1 hour, 60% to 80% within 2 hours, 80% to 100% within 5 hours, and / or 90% to 100% within 8 hours, where the percentages are based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition (immediate-release and controlled-release pharmaceutical granules). The components and dissolution conditions of the pharmaceutical composition are provided in Examples 2 and 4.

[0349] Pharmaceutical granules containing immediate-release granules and controlled-release granules, as well as pharmaceutical compositions containing excipient granules, immediate-release granules, and controlled-release granules, can exhibit a dissolution profile in which 45% to 55% of 4-((L-valyl)oxy)butanoic acid is released into the dissolving solvent within 1 hour, 65% to 75% within 2 hours, 85% to 95% within 5 hours, and / or 90% to 100% within 9 hours, where the percentages are based on the total amount of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical granules (immediate-release and controlled-release pharmaceutical granules). Dissolution conditions for 4-((L-valyl)oxy)butanoic acid are provided in Examples 2 and 4.

[0350] Pharmaceutical compositions comprising excipient granules, immediate-release granules, and controlled-release granules can exhibit a 4-((L-valyl)oxy)butanoic acid solubility profile that is biologically equivalent to the solubility profile shown in Figure 5. The 4-((L-valyl)oxy)butanoic acid solubility conditions are provided in Example 4.

[0351] The products provided by this disclosure may include excipient granules provided by this disclosure contained within a package. The package may be any suitable package, such as a container, sachet, blister pack, or ampoule.

[0352] The pharmaceutical products provided by this disclosure may include excipient granules and pharmaceutical granules contained within a primary package.

[0353] The primary packaging may include any packaging suitable for use with the pharmaceutical granules. Examples of suitable primary packaging include blister packs, sachets, pouches, capsules, ampoules, and vials.

[0354] In pharmaceuticals, excipient granules and pharmaceutical granules can be contained within the same primary package.

[0355] In pharmaceuticals, excipient granules and pharmaceutical granules can be housed in separate primary packages.

[0356] In pharmaceuticals, immediate-release drug granules and controlled-release drug granules can be housed in separate primary packages or in the same primary package.

[0357] In pharmaceuticals, a package may contain a unit dose of 4-((L-valyl)oxy)butanoic acid or less than a unit dose of 4-((L-valyl)oxy)butanoic acid. In pharmaceuticals that include a package such as a sachet containing less than a unit dose of an active pharmaceutical ingredient, the pharmaceutical may contain two or more packages containing 4-((L-valyl)oxy)butanoic acid such that the total amount of 4-((L-valyl)oxy)butanoic acid in two or more primary packages constitutes a unit dose of 4-((L-valyl)oxy)butanoic acid.

[0358] The pharmaceutical product may include one or a compartment containing excipient granules and pharmaceutical granules. The compartment may be a blister pack.

[0359] Excipient granules and pharmaceutical granules can be housed in the same compartment of the package.

[0360] Each of the excipient granules and the pharmaceutical granules can be housed in separate, independent compartments within a common package. For example, the package may include a first compartment for the excipient granules and a second compartment for the pharmaceutical granules.

[0361] The pharmaceutical product may include a compartment for containing excipient granules and a second compartment for containing pharmaceutical granules, the compartments configured to be mixed before or during mixing with the aqueous solution.

[0362] The pharmaceutical product provided by this disclosure may include a first package containing excipient granules provided by this disclosure, and a second package containing pharmaceutical granules.

[0363] The pharmaceutical product may include a sachet containing both the excipient granules and the pharmaceutical granules provided by this disclosure.

[0364] Pharmaceuticals may include combinations of excipient granules and pharmaceutical granules ranging from 0.5g to 30g, such as combinations of excipient granules and pharmaceutical granules in amounts of 1g to 25g, 1g to 20g, 2g to 15g, 2g to 10g, 2g to 5g, or 1g to 5g.

[0365] The pharmaceutical products provided by this disclosure may contain a unit dose of 4-((L-valyl)oxy)butanoic acid.

[0366] A unit dose of 4-((L-valyl)oxy)butanoic acid can be supplied in one or more packages, such as one or more sachets.

[0367] The pharmaceutical products provided by this disclosure may contain one or more unit doses of 4-((L-valyl)oxy)butanoic acid. Each of the one or more unit doses may be provided in separate packaging, such as separate sachets.

[0368] The unit dose may be suitable for treating the patient's disease.

[0369] The oral pharmaceutical compositions provided by this disclosure can deliver a therapeutically effective amount of gamma-hydroxybutyrate into a patient's plasma over a period of time. For example, the oral formulations provided by this disclosure can deliver a therapeutically effective amount of gamma-hydroxybutyrate over a period of 3 hours, 6 hours, 8 hours, or 10 hours.

[0370] The oral pharmaceutical compositions provided by this disclosure can provide a therapeutically effective amount of gamma-hydroxybutyrate over periods of 4 to 12 hours, 4 to 10 hours, or 4 to 8 hours.

[0371] The oral pharmaceutical compositions provided by this disclosure can provide, for example, a therapeutically effective amount of γ-hydroxybutyrate over a period of 1 to 12 hours after oral administration, over a period of 2 to 10 hours or 4 to 8 hours after oral administration.

[0372] The oral pharmaceutical compositions provided by this disclosure may be a once-night formulation. For a once-night formulation, a patient is administered a certain dose of crystalline 4-((L-valyl)oxy)butanoic acid and / or γ-hydroxybutyrate as the prodrug provided by this disclosure before bedtime and can sleep through the night for six or eight hours, etc., without administering a second dose during the night.

[0373] The oral pharmaceutical compositions provided by this disclosure can deliver a therapeutically effective amount of gamma-hydroxybutyrate into a patient's plasma. The oral pharmaceutical compositions provided by this disclosure can deliver a therapeutically effective amount of gamma-hydroxybutyrate into a patient's plasma over a period of 4, 6, 8, or 10 hours after oral administration of a controlled-release oral pharmaceutical composition.

[0374] The oral pharmaceutical compositions provided by this disclosure can provide a plasma concentration of γ-hydroxybutyrate greater than, for example, 10 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the oral pharmaceutical composition.

[0375] The oral pharmaceutical compositions provided by this disclosure can provide a plasma concentration of γ-hydroxybutyrate greater than, for example, 15 μg / mL for more than 4 hours, more than 6 hours, more than 8 hours, or more than 10 hours after oral administration of the oral pharmaceutical composition.

[0376] The oral formulations provided by this disclosure release a therapeutically effective amount of γ-hydroxybutyrate in the patient's plasma for a period of 4, 6, 8, or 10 hours after oral administration of the controlled-release oral pharmaceutical composition. 最大 vs C 最小 The ratio can be provided, for example, as less than 3 or less than 2.

[0377] The oral pharmaceutical compositions provided by this disclosure may contain 4-((L-valyl)oxy)butanoic acid, such as crystalline 4-((L-valyl)oxy)butanoic acid, and may include, for example, 0.5 g equivalent, 1 g equivalent, 2 g equivalent, 3 g equivalent, 4 g equivalent, 5 g equivalent, 6 g equivalent, 7 g equivalent, 8 g equivalent, 9 g equivalent, 10 g equivalent, 11 g equivalent, or 12 g equivalent of γ-hydroxybutyric acid. The oral pharmaceutical compositions provided by this disclosure may contain crystalline 4-((L-valyl)oxy)butanoic acid, and may include, for example, 0.5 g equivalent to 12 g equivalent of γ-hydroxybutyric acid, 1 g equivalent to 12 g equivalent, 2 g equivalent to 12 g equivalent, 3 g equivalent to 11 g equivalent, 4 g equivalent to 10 g equivalent, or 5 g equivalent to 9 g equivalent of γ-hydroxybutyric acid. The oral pharmaceutical compositions provided by this disclosure may, for example, include gamma-hydroxybutyrate in amounts exceeding 0.5 g equivalent, 1 g equivalent, 3 g equivalent, 5 g equivalent, 7 g equivalent, 9 g equivalent, or 11 g equivalent.

[0378] The oral pharmaceutical compositions provided by this disclosure may include suspensions such as aqueous suspensions of immediate-release pharmaceutical granules and controlled-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid. The cores of the immediate-release pharmaceutical granules and controlled-release pharmaceutical granules may contain more than 90% by weight of 4-((L-valyl)oxy)butanoic acid, such as more than 94% by weight or more than 96% by weight, where the weight percentage is based on the total weight of the core of the immediate-release pharmaceutical granules or controlled-release pharmaceutical granules.

[0379] The oral pharmaceutical compositions provided by this disclosure can be provided as sachets or packages containing, for example, an immediate-release component such as an immediate-release pharmaceutical granule containing 4-((L-valyl)oxy)butanoic acid and a controlled-release component such as a controlled-release pharmaceutical granule containing 4-((L-valyl)oxy)butanoic acid. The sachets or packages may be provided in different dose equivalents of γ-hydroxybutyric acid, for example, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 10 g, 12 g, 15 g, or 20 g equivalents of γ-hydroxybutyric acid.

[0380] Oral dosage forms such as coated granules containing immediate-release granules and controlled-release granules can be mixed with water, for example, to provide an orally ingestible dosage form.

[0381] Following oral administration of the oral formulation provided by this disclosure and absorption of 4-((L-valyl)oxy)butanoic acid in the gastrointestinal tract, it can be metabolized in the patient's systemic circulation to provide γ-hydroxybutyrate.

[0382] The method provided by this disclosure comprises providing a therapeutically effective amount of gamma-hydroxybutyrate into the systemic circulation of a patient to treat a patient's disease or disorder or symptoms of a patient's disease or disorder, which comprises administering to the patient an oral formulation provided by this disclosure comprising 4-((L-valyl)oxy)butanoic acid.

[0383] Preferred doses of 4-((L-valyl)oxy)butanoic acid can provide doses of γ-hydroxybutyric acid in amounts of 1 to 12 gram equivalents, for example, 1 to 10 gram equivalents, 2 to 9 gram equivalents, 3 to 8 gram equivalents, or 4 to 7 gram equivalents.

[0384] However, it should be understood that the specific dose level and frequency of administration for any given patient will vary and depend on various factors, including metabolic stability and duration of action, age, weight, overall health status, sex, diet, method and timing of administration, excretion rate, drug combinations, severity of the particular condition, and the host being treated.

[0385] When initiating treatment with 4-((L-valyl)oxy)butanoic acid, titrating to an appropriate plasma concentration can help achieve favorable results and avoid adverse effects. For example, the dosage can be divided into two doses of 4.5 g equivalent of gamma-hydroxybutyrate, with the first dose taken at bedtime and the second 2.5 to 4 hours later. The starting dose can be reduced by 1.5 g / day (0.75 g per dose) up to 3.0 g / day, or increased by 1.5 g / day (0.75 g per dose) up to 9.0 g / day. A single dose can provide sufficient 8 hours of sleep, but after 8 hours, very little gamma-hydroxybutyrate remains in the patient's plasma.

[0386] The oral pharmaceutical formulations provided by this disclosure may be configured to provide a single nighttime dose, once daily dose (QD), twice daily dose (BID), three times daily dose (TID), or four times daily dose (QID). For example, a pharmaceutical composition comprising a controlled-release granule may release substantially 100% crystalline 4-((L-valyl)oxy)butanoic acid over a duration of 24 hours, 12 hours, 8 hours, or 4 hours.

[0387] 4-((L-valyl)oxy)butanoic acid is a prodrug of gamma-hydroxybutyrate. 4-((L-valyl)oxy)butanoic acid can be used to treat any disease or disorder that is known to be treated by gamma-hydroxybutyrate or has been determined to be treated by gamma-hydroxybutyrate.

[0388] For example, 4-((L-valyl)oxy)butanoic acid can be used to treat narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and fibromyalgia.

[0389] 4-((L-valyl)oxy)butanoic acid can be used to treat REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, symptoms of Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, and anxiety disorders.

[0390] 4-((L-valyl)oxy)butanoic acid can be used to treat excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue in patients with Parkinson's disease, fatigue in patients with multiple sclerosis, or fibromyalgia.

[0391] 4-((L-valyl)oxy)butanoic acid and its pharmaceutical compositions can be used to treat sleep disorders such as apnea, sleep duration disorders, narcolepsy, cataplexy, sleep paralysis, hypnagogic hallucinations, sleep-wake cycles, insomnia, and nocturnal myoclonus.

[0392] 4-((L-valyl)oxy)butanoic acid or its pharmaceutical composition can be used to treat a selection of diseases from narcolepsy, cataplexy, cataplexy with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, symptoms of Parkinson's disease, neurodegenerative diseases, sleep disorder syndromes, fatigue, improvement of nocturnal sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal and dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, difficulty falling asleep and maintaining sleep, chronic fatigue syndrome, essential tremor, hemiplegia in children with alternating hemiplegia, sedative abuse, and binge eating disorder.

[0393] For certain treatment methods, the effectiveness of the treatment can be measured by one or more of the following criteria: an increase in mean sleep latency as determined by the Maintenance of Wakefulness Test (MWT); an improvement in the Clinical Global Impression (CGI) assessment of sleepiness; a decrease in the number of cataplexy (NCAs) as determined by the cataplexy frequency item in the sleep and symptom diary; a decrease in nocturnal sleep disturbances (DNS), nocturnal disturbance events, or adverse respiratory events as determined by the polysomnography (PSG) scale for sleep fragmentation; a decrease in excessive daytime sleepiness (EDS) as measured by the Epworth Sleepiness Scale (ESS); a decrease in daytime sleepiness as measured by the Maintenance of Wakefulness Test based on the EEG scale for the state of wakefulness; a decrease in PSG transitions from N / 2 to N / 3, as well as PSG transitions from REM sleep to wakefulness and N1 sleep, as determined as described in the AASM Manual for the Scoring of Sleep and Associated Events; and the American Academy of Sleep Medicine A reduction in the number of awakenings or wakefulness as determined from PSG as defined by Medicine; an improvement in sleep quality as determined using (i) sleep and symptom diaries, (ii) visual analog scales (VAS) for sleep quality and sleep diaries, and / or (iii) VAS for good quality sleep; and a reduction in hypnagogic hallucinations (HH) or sleep paralysis (SP) symptoms in NT1 narcolepsy patients as measured by sleep and symptom diaries.

[0394] Type 1 narcolepsy (NT1) refers to narcolepsy characterized by excessive daytime sleepiness ("EDS") and cataplexy. Type 2 narcolepsy (NT2) refers to narcolepsy characterized by excessive daytime sleepiness without cataplexy. A diagnosis of narcolepsy (with or without cataplexy) can be confirmed by (i) a polysomnography (PSG) and multiple sleep latency test (MSLT) performed within the past two years, (ii) complete documented evidence confirming the diagnosis from the PSG and MSLT from the Sleep Institute, (iii) current symptoms of narcolepsy, including current complaints of EDS (Epworth Sleepiness Scale (ESS) > 10) for the past three months, (iv) a mean maintenance of wakefulness test (MWT) of less than eight minutes, (v) a mean number of cataplexy events of eight per week in a baseline sleep / cataplexy diary, and / or (vi) the presence of cataplexy in the past three months and one or a combination of 28 events per week during the screening period.

[0395] manner The present invention is further defined by one or more of the following embodiments.

[0396] Embodiment 1.4 A pharmaceutical composition comprising a pharmaceutical granule containing ((L-valyl)oxy)butanoic acid and an excipient granule.

[0397] Embodiment 2. The pharmaceutical composition according to Embodiment 1, wherein the pharmaceutical granules contain 1 g to 20 g of 4-((L-valyl)oxy)butanoic acid.

[0398] Embodiment 3. The pharmaceutical composition according to any one of Embodiments 1 to 2, wherein the pharmaceutical composition comprises 2% to 12% by weight of the excipient granules, and the weight percentage is based on the total weight of the pharmaceutical composition.

[0399] Embodiment 4. The pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the pharmaceutical composition comprises 86% to 98% by weight of the pharmaceutical granules, and the weight percentage is based on the total weight of the pharmaceutical composition.

[0400] Embodiment 5. The pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the pharmaceutical granules comprise an immediate-release pharmaceutical granule comprising a plurality of immediate-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid, and a modified-release pharmaceutical granule comprising a plurality of modified-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid.

[0401] Embodiment 6. The pharmaceutical composition according to any one of Embodiments 1 to 5, wherein the pharmaceutical granules comprise 17% to 37% by weight of the immediate-release pharmaceutical granules and 64% to 74% by weight of the controlled-release pharmaceutical granules, and the weight percentage is based on the total weight of the pharmaceutical granules.

[0402] Embodiment 7. The pharmaceutical composition according to any one of Embodiments 1 to 6, wherein the immediate-release pharmaceutical granules contain 2.5 g to 6.5 g of 4-((L-valyl)oxy)butanoic acid, and the adjusted-release pharmaceutical granules contain 8 g to 12 g of 4-((L-valyl)oxy)butanoic acid.

[0403] Embodiment 8. The pharmaceutical composition according to any one of Embodiments 1 to 7, wherein the immediate-release pharmaceutical granules contain 26% to 36% by weight of the 4-((L-valyl)oxy)butanoic acid, and the adjusted-release pharmaceutical granules contain 64% to 74% by weight of the 4-((L-valyl)oxy)butanoic acid, and the weight percentage is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition.

[0404] Embodiment 9. The pharmaceutical composition according to any one of Embodiments 1 to 8, wherein the ratio of the weight of 4-((L-valyl)oxy)butanoic acid in the adjusted release granules to the weight of 4-((L-valyl)oxy)butanoic acid in the immediate release granules is 1.7 to 3.7.

[0405] Embodiment 10. The pharmaceutical composition according to any one of Embodiments 1 to 9, wherein the pharmaceutical composition comprises 15% to 35% by weight of the immediate-release pharmaceutical granules, 55% to 75% by weight of the adjusted-release pharmaceutical granules, and 2% to 12% by weight of the excipient granules, the weight percentage being based on the total weight of the pharmaceutical composition.

[0406] Embodiment 11. The pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the pharmaceutical composition contains 65% to 85% by weight of the 4-((L-valyl)oxy)butanoic acid, and the weight percentage is based on the total weight of the pharmaceutical composition.

[0407] Embodiment 12. The pharmaceutical composition according to any one of Embodiments 1 to 11, wherein the pharmaceutical composition has a weight of 2 g to 30 g.

[0408] Embodiment 13. The pharmaceutical composition according to any one of Embodiments 5 to 12, wherein the uncoated immediate-release pharmaceutical granules contain 85% to 95% by weight of 4-((L-valyl)oxy)butanoic acid.

[0409] Embodiment 14. The pharmaceutical composition according to Embodiment 13, wherein the uncoated immediate-release pharmaceutical granules contain 1% to 9% by weight of a water-soluble polymer.

[0410] Embodiment 15. The pharmaceutical composition according to Embodiment 14, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose.

[0411] Embodiment 16. The pharmaceutical composition according to any one of Embodiments 13 to 15, wherein the uncoated immediate-release pharmaceutical granules contain 1% to 9% by weight of an antistatic agent.

[0412] Embodiment 17. The pharmaceutical composition according to Embodiment 16, wherein the antistatic agent comprises a hydrated magnesium silicate.

[0413] Embodiment 18. The pharmaceutical composition according to any one of Embodiments 13 to 17, wherein the uncoated immediate-release pharmaceutical granules have a homogeneous composition.

[0414] Embodiment 19. The pharmaceutical composition according to any one of Embodiments 13 to 18, wherein the immediate-release pharmaceutical granules include a seal coat surrounding the uncoated immediate-release pharmaceutical granules.

[0415] Embodiment 20. The pharmaceutical composition according to any one of Embodiments 13 to 19, wherein the immediate-release pharmaceutical granules have an average diameter of 100 μm to 600 μm, and the average diameter is determined by sieve analysis or laser diffraction.

[0416] Embodiment 21. The pharmaceutical composition according to any one of Embodiments 13 to 20, wherein the immediate-release pharmaceutical granules have an average bulk density of 0.40 g / mL to 1.60 g / mL, and the average bulk density is determined using a bulk density cylinder.

[0417] Embodiment 22. The pharmaceutical composition according to any one of Embodiments 13 to 21, wherein the immediate-release pharmaceutical granules have an average bulk density of 0.40 g / mL to 1.00 g / mL, and the average bulk density is determined using a bulk density cylinder.

[0418] Embodiment 23. The pharmaceutical composition according to any one of Embodiments 13 to 22, wherein the immediate-release pharmaceutical granules include a seal coating.

[0419] Embodiment 24. The pharmaceutical composition according to any one of Embodiments 13 to 23, wherein the immediate-release pharmaceutical granules have a sphericity of 0.90 to 1.00, and the sphericity is determined by using a wet dispersion particle shape method or by dynamic image analysis.

[0420] Embodiment 25. The pharmaceutical composition according to any one of Embodiments 13 to 24, wherein the immediate-release pharmaceutical granules have an abrasion degree of 0.9 to 1.0, and the average abrasion degree is determined using an ultrasonic sieve.

[0421] Embodiment 26. The pharmaceutical composition according to any one of Embodiments 13 to 25, wherein the immediate-release pharmaceutical granules are configured to dissolve completely in water within 5 minutes.

[0422] Embodiment 27. The pharmaceutical composition according to any one of Embodiments 13 to 26, wherein the immediate-release pharmaceutical granules dissolve completely in water in less than one minute.

[0423] Embodiment 28. The pharmaceutical composition according to any one of Embodiments 13 to 27, wherein the immediate-release pharmaceutical granules have a dissolution profile as shown in Figure 1.

[0424] Embodiment 29. The pharmaceutical composition according to any one of Embodiments 5 to 28, wherein the controlled-release pharmaceutical granules include an immediate-release granule and a controlled-release coating surrounding the immediate-release granule.

[0425] Embodiment 30. The pharmaceutical composition according to any one of Embodiments 5 to 29, wherein the adjusted-release pharmaceutical granules comprise 70% to 90% by weight of the immediate-release granules, and the weight percentage is based on the total weight of the adjusted-release pharmaceutical granules.

[0426] Embodiment 31. The pharmaceutical composition according to any one of Embodiments 5 to 30, wherein the adjusted-release pharmaceutical granules contain 10% to 30% by weight of the adjusted-release coating, and the weight percentage is based on the total weight of the adjusted-release pharmaceutical granules.

[0427] Embodiment 32. The pharmaceutical composition according to any one of Embodiments 5 to 31, wherein the adjusted-release pharmaceutical granules contain 65% to 85% by weight of 4-((L-valyl)oxy)butanoic acid, and the weight percentage is based on the total weight of the adjusted-release pharmaceutical granules.

[0428] Embodiment 33. The pharmaceutical composition according to any one of Embodiments 29 to 32, wherein the immediate-release granules include uncoated immediate-release pharmaceutical granules.

[0429] Embodiment 34. The pharmaceutical composition according to any one of Embodiments 29 to 33, wherein the adjusted release coating comprises 63% to 83% by weight of a water-insoluble polymer, the weight percentage being based on the total weight of the adjusted release coating.

[0430] Embodiment 35. The pharmaceutical composition according to Embodiment 34, wherein the water-insoluble polymer comprises ethylcellulose.

[0431] Embodiment 36. The pharmaceutical composition according to any one of Embodiments 29 to 35, wherein the adjusted release coating comprises 2% to 6% by weight of a water-soluble polymer, and the weight percentage is based on the total weight of the adjusted release coating.

[0432] Embodiment 37. The pharmaceutical composition according to Embodiment 36, wherein the water-soluble polymer comprises hydroxypropyl cellulose.

[0433] Embodiment 38. The pharmaceutical composition according to any one of Embodiments 5 to 37, wherein the adjusted release coating contains 6% to 10% by weight of a lubricant, and the weight percentage is based on the total weight of the adjusted release coating.

[0434] Embodiment 39. The pharmaceutical composition according to Embodiment 38, wherein the lubricant comprises dibutyl sebacate.

[0435] Embodiment 40. The pharmaceutical composition according to any one of Embodiments 5 to 39, wherein the adjusted release coating contains 10% to 20% by weight of an antistatic agent, and the weight percentage is based on the total weight of the adjusted release coating.

[0436] Embodiment 41. The pharmaceutical composition according to Embodiment 40, wherein the antistatic agent comprises a hydrated magnesium silicate.

[0437] Embodiment 42. The pharmaceutical composition according to any one of Embodiments 29 to 33, wherein the adjusted release coating comprises a water-insoluble polymer, a water-soluble polymer, a lubricant, and an antistatic agent.

[0438] Embodiment 43. The pharmaceutical composition according to Embodiment 42, wherein the adjusted release coating comprises 63% to 83% by weight of a water-insoluble polymer, 2% to 10% by weight of a water-soluble polymer, 6% to 10% by weight of a lubricant, and 10% to 20% by weight of an antistatic agent, the weight percentage being based on the total weight of the adjusted release coating.

[0439] Embodiment 44. The pharmaceutical composition according to any one of Embodiments 42 to 33, wherein the water-insoluble polymer comprises ethylcellulose, the water-soluble polymer comprises hydroxypropylcellulose, the lubricant comprises dibutyl sebacate, and the antistatic agent comprises hydrated magnesium silicate.

[0440] Embodiment 45. The pharmaceutical composition according to any one of Embodiments 29 to 44, wherein the adjusted release coating has a thickness of 5 μm to 40 μm.

[0441] Embodiment 46. The pharmaceutical composition according to any one of Embodiments 5 to 45, wherein the adjusted-release pharmaceutical granules are characterized by an average particle size of 100 μm to 600 μm, and the average particle size is determined by sieve analysis or laser diffraction.

[0442] Embodiment 47. The pharmaceutical composition according to any one of Embodiments 5 to 46, wherein the adjusted-release pharmaceutical granules are configured to continuously release the 4-((L-valyl)oxy)butanoic acid over time in the gastrointestinal tract.

[0443] Embodiment 48. The pharmaceutical composition according to any one of Embodiments 5 to 47, wherein the adjusted-release pharmaceutical granules have a dissolution profile characterized by 40% to 60% dissolution within 1 hour and 60% to 80% dissolution within 2 hours, and the dissolution is determined using a USP Type 2 dissolution apparatus with a buffer solution of pH 4.5 at a temperature of 37°C and a paddle speed of 75 rpm.

[0444] Embodiment 49. The pharmaceutical composition according to any one of Embodiments 5 to 48, wherein the adjusted-release pharmaceutical granules have a dissolution profile as shown in Figure 3.

[0445] Embodiment 50. The excipient granules comprising a plurality of excipient granules, and the excipient granules comprising a viscous agent, a disintegrant, and one or more additional excipients, according to any one of Embodiments 1 to 49.

[0446] Embodiment 51. The pharmaceutical composition according to Embodiment 50, wherein the excipient granules comprise 1% to 35% by weight of the viscous agent, 1% to 25% by weight of the disintegrant, and 40% to 98% by weight of one or more additional excipients, the weight percentage being based on the total weight of the excipient granules.

[0447] Embodiment 52. The pharmaceutical composition according to Embodiment 50, wherein the excipient granules comprise 5% to 15% by weight of the viscous agent, 5% to 20% by weight of the disintegrant, and 65% to 90% by weight of one or more additional excipients, the weight percentage being based on the total weight of the excipient granules.

[0448] Embodiment 53. The pharmaceutical composition according to any one of Embodiments 1 to 52, wherein the excipient granules have a homogeneous composition.

[0449] Embodiment 54. The pharmaceutical composition according to any one of Embodiments 1 to 53, wherein the excipient granules have an average particle size of 100 μm to 600 μm, and the particle size is determined by sieve analysis or laser diffraction.

[0450] Embodiment 55. The pharmaceutical composition according to any one of Embodiments 1 to 54, wherein the excipient granules have an average bulk density of 0.5 g / mL to 0.7 g / mL, and the bulk density is determined according to USP616, Method 1.

[0451] Embodiment 56. The pharmaceutical composition according to any one of Embodiments 50 to 55, wherein the viscous agent comprises xanthan gum.

[0452] Embodiment 57. The pharmaceutical composition according to Embodiment 56, wherein the xanthan gum has an average particle size of 25 μm to 100 μm, and the particle size is determined using sieve analysis or laser diffraction.

[0453] Embodiment 58. The pharmaceutical composition according to Embodiment 56, wherein the xanthan gum has an average particle size of less than 75 μm, and the particle size is determined by sieve analysis or laser diffraction.

[0454] Aspect 59. The pharmaceutical composition according to any one of Aspects 56 to 58, wherein the xanthan gum has a viscosity ratio of 1.0 to 1.5.

[0455] Aspect 60. The pharmaceutical composition according to any one of Aspects 56 to 59, wherein the xanthan gum provides a viscosity of 1,200 mPa×sec to 1600 mPa×sec (cP).

[0456] Aspect 61. The pharmaceutical composition according to any one of Aspects 50 to 60, wherein the disintegrant contains crospovidone.

[0457] Aspect 62. The excipient granulate according to Aspect 61, wherein the crospovidone has a pH value of 5 to 8, a bulk density of 0.25 g / cm 3 to 0.45 g / cm 3 as a 1% solution in water at 25°C, and / or an average particle size of 20 μm to 40 μm.

[0458] Aspect 63. The pharmaceutical composition according to any one of Aspects 50 to 62, wherein the one or more additional excipients include a diluent, a binder, a flavoring agent, a buffering agent, an acid, a sweetening agent, a filler, or any combination of the foregoing.

[0459] Aspect 64. The pharmaceutical composition according to any one of Aspects 50 to 63, wherein the one or more additional excipients include a binder.

[0460] Aspect 65. The pharmaceutical composition according to Aspect 64, wherein the binder contains polyvinylpyrrolidone.

[0461] Aspect 66. The pharmaceutical composition according to Aspect 65, wherein the polyvinylpyrrolidone has a K value of 29 to 32, a number average molecular weight of 58,000 daltons, a viscosity of 2.5 cP in a 5% aqueous solution at 25°C, an average particle size of 80 μm, a bulk density of 0.36 g / cm 3 and / or a tap density of 0.47 g / cm 3

[0462] Embodiment 67. The pharmaceutical composition according to any one of Embodiments 64 to 66, wherein the excipient granules contain 5% to 20% by weight of a binder, and the weight percentage is based on the total weight of the excipient granules.

[0463] Embodiment 68. The pharmaceutical composition according to any one of Embodiments 50 to 67, wherein the one or more additional excipients include a diluent.

[0464] Embodiment 69. The pharmaceutical composition according to Embodiment 68, wherein the diluent contains anhydrous dibasic calcium phosphate.

[0465] Embodiment 70. The pharmaceutical composition according to any one of Embodiments 68 to 69, wherein the excipient granules contain 10% to 30% by weight of the diluent, and the weight percentage is based on the total weight of the excipient granules.

[0466] Embodiment 71. The pharmaceutical composition according to any one of Embodiments 50 to 70, wherein the one or more additional excipients include a filler.

[0467] Embodiment 72. The pharmaceutical composition according to Embodiment 71, wherein the filler comprises microcrystalline cellulose.

[0468] Embodiment 73. The pharmaceutical composition according to any one of Embodiments 71 to 72, wherein the excipient granules contain 1% to 20% by weight of a binder, and the weight percentage is based on the total weight of the excipient granules.

[0469] Embodiment 74. The pharmaceutical composition according to any one of Embodiments 50 to 73, wherein the one or more additional excipients include a flavoring agent.

[0470] Embodiment 75. The pharmaceutical composition according to Embodiment 74, wherein the flavoring agent comprises a citrus fruit flavoring agent, a berry flavoring agent, a punch flavoring agent, or any combination thereof.

[0471] Embodiment 76. The pharmaceutical composition according to any one of Embodiments 74 to 75, wherein the excipient granules contain 15% to 35% by weight of the flavoring agent, and the weight percentage is based on the total weight of the excipient granules.

[0472] Embodiment 77. The pharmaceutical composition according to any one of Embodiments 50 to 76, wherein the one or more additional excipients include a buffering agent.

[0473] Embodiment 78. The pharmaceutical composition according to Embodiment 77, wherein the buffering agent comprises anhydrous sodium citrate.

[0474] Embodiment 79. The pharmaceutical composition according to any one of Embodiments 77 to 278, wherein the excipient granules contain 0.5% to 6.5% by weight of a buffer, and the weight percentage is based on the total weight of the excipient granules.

[0475] Embodiment 80. The pharmaceutical composition according to any one of Embodiments 50 to 79, wherein the one or more additional excipients include an acid.

[0476] Embodiment 81. The pharmaceutical composition according to Embodiment 80, wherein the acid comprises citric acid anhydride.

[0477] Embodiment 82. The pharmaceutical composition according to any one of Embodiments 80 to 81, wherein the excipient granules contain 0.5% to 8% by weight of the acid, and the weight percentage is based on the total weight of the excipient granules.

[0478] Embodiment 83. The pharmaceutical composition according to any one of Embodiments 50 to 82, wherein the one or more additional excipients include a sweetener.

[0479] Embodiment 84. The pharmaceutical composition according to Embodiment 83, wherein the sweetener comprises sucralose.

[0480] Embodiment 85. The pharmaceutical composition according to any one of Embodiments 83 to 84, wherein the excipient granules contain 0.1% to 6% by weight of the sweetener, and the weight percentage is based on the total weight of the excipient granules.

[0481] Embodiment 86. The pharmaceutical composition according to Embodiment 63, wherein the excipient granules comprise 2% to 22% by weight of the binder, 10% to 30% by weight of the diluent, 1% to 20% by weight of the filler, 15% to 35% by weight of the flavoring agent, 0.5% to 6.5% by weight of the buffer, 0.5% to 8% by weight of the acid, and / or 0.1% to 6% by weight of the sweetener, and the weight percentage is based on the total weight of the excipient granules.

[0482] Embodiment 87. The pharmaceutical composition according to Embodiment 86, wherein the excipient granules contain 1% to 35% by weight of the viscous agent and 1% to 25% by weight of the disintegrant, and the weight percentage is based on the total weight of the excipient granules.

[0483] Embodiment 88. The pharmaceutical composition according to any one of Embodiments 86 to 87, wherein the excipient granules comprise 5% to 15% by weight of the binder, 17% to 27% by weight of the diluent, 6% to 16% by weight of the filler, 20% to 30% by weight of the flavoring agent, 1% to 5% by weight of the buffer, 2% to 6% by weight of the acid, and / or 1% to 5% by weight of the sweetener, and the weight percentage is based on the total weight of the excipient granules.

[0484] Embodiment 89. The pharmaceutical composition according to Embodiment 88, wherein the excipient granules contain 5% to 15% by weight of the viscous agent and 7% to 17% by weight of the disintegrant, and the weight percentage is based on the total weight of the excipient granules.

[0485] Embodiment 90. A pharmaceutical composition according to any one of Embodiments 88 to 89, wherein the viscosifying agent comprises xanthan gum, the disintegrant comprises crospovidone, the binder comprises polyvinylpyrrolidone, the diluent comprises dicalcium phosphate, the filler comprises microcrystalline cellulose, the flavoring agent comprises a berry / punch flavoring agent, the buffering agent comprises sodium citrate dihydrate, the acid comprises citric acid anhydride, and the sweetener comprises sucralose, and the weight % is based on the total weight of the excipient granules.

[0486] Embodiment 91. The pharmaceutical composition according to any one of any one embodiment of Embodiments 50 to 90, wherein the excipient granules have an average particle size of 100 μm to 600 μm, and the particle size is determined by sieve analysis or laser diffraction.

[0487] Embodiment 92. The pharmaceutical composition according to any one of Embodiments 50 to 91, wherein the excipient granules have a particle size distribution characterized by 8.5% by weight of particles with a mesh size greater than 35 (500 μm), 39% by weight of particles with a mesh size of 35 to 60 (500 to 250 μm), 52.2% of particles with a pan (pane) particle size, and 52.2% by weight of particles with a particle size less than 35 (500 μm), and the particle size is determined by sieve analysis or laser diffraction.

[0488] Embodiment 93. The pharmaceutical composition according to any one of Embodiments 1 to 92, wherein the excipient granules (35-60 mesh fraction) have an average bulk density of 0.5 g / mL to 0.9 g / mL, and the bulk density is determined using a bulk density cylinder.

[0489] Embodiment 94. The pharmaceutical composition according to any one of Embodiments 1 to 93, wherein the excipient granules have an average bulk density of 0.6 g / mL to 0.7 g / mL (35 to 60 mesh fractions), and the bulk density is determined using a bulk density cylinder.

[0490] Embodiment 95. The pharmaceutical composition according to any one of Embodiments 1 to 94, wherein the excipient granules dissolve completely in less than 60 seconds when re-prepared in water at 25°C.

[0491] Embodiment 96. The pharmaceutical composition according to any one of Embodiments 1 to 95, wherein the excipient granules dissolve completely in less than 30 seconds when re-prepared in water at 25°C.

[0492] Embodiment 97. The pharmaceutical composition according to any one of Embodiments 1 to 96, wherein the excipient granules dissolve completely in less than 60 seconds when prepared as a 1 w / v% solution in water at 25°C.

[0493] Embodiment 98. The pharmaceutical composition according to any one of Embodiments 1 to 97, wherein the excipient granules dissolve completely in less than 30 seconds when prepared as a 1 w / v% solution in water at 25°C.

[0494] Embodiment 99. The excipient granules have an average Hausner ratio of 1.1 to 1.25, and the Hausner ratio is USP <1174> A pharmaceutical composition according to any one of embodiments 1 to 98, determined according to the following.

[0495] Embodiment 100. A pharmaceutical granule according to any one of Embodiments 1 to 99, wherein the excipient granule has an average compressibility index of 12 to 18.

[0496] Embodiment 101. The pharmaceutical composition according to any one of Embodiments 1 to 100, wherein the excipient granules have an average Flodex value of less than 5 mm.

[0497] Embodiment 102. The pharmaceutical composition according to any one of Embodiments 1 to 101, wherein the excipient granules have an average abrasion degree of less than 2% by weight, and the abrasion degree is determined using an ultrasonic sieve.

[0498] Embodiment 103. The pharmaceutical composition according to any one of Embodiments 1 to 102, wherein the excipient granules provide a pH of 4.0 to 8.0 when prepared as a 1 w / v% solution in water.

[0499] The pharmaceutical composition according to any one of embodiments 1 to 103, wherein when 1.2 g of the excipient granules is re-prepared in 40 mL of water at 25°C, the resulting solution exhibits a viscosity-to-time profile as shown in Figure 2.

[0500] The pharmaceutical composition according to any one of embodiments 1 to 104, wherein when 2 g of the excipient granules is re-prepared in 40 mL of water at 25°C, the resulting solution exhibits a brightness-to-time profile as shown in Figure 3.

[0501] A pharmaceutical composition according to any one of embodiments 1 to 105, wherein a solution of 2 g of the excipient granules and 40 mL of water is mixed at 25°C for 90 seconds, and the solution has a viscosity in the range of 45 cP to 80 cP.

[0502] A pharmaceutical composition according to any one of embodiments 1 to 106, wherein a solution of 2 g of the excipient granules and 40 mL of water is mixed at 25°C for 30 seconds, and the solution has a viscosity in the range of 15 cP to 40 cP.

[0503] A pharmaceutical composition according to any one of embodiments 1 to 107, wherein a solution of 2 g of the excipient granules and 40 mL of water is mixed at 25°C for 60 seconds, and the solution has a viscosity in the range of 35 cP to 60 cP.

[0504] Embodiment 109. The pharmaceutical composition according to any one of Embodiments 50 to 108, wherein the excipient granules have a dissolution profile characterized by complete dissolution within 30 seconds.

[0505] Embodiment 110. The pharmaceutical composition according to any one of Embodiments 50 to 109, wherein the excipient granules have a solubility profile as shown in Figure 4.

[0506] Embodiment 111. The pharmaceutical composition according to any one of Embodiments 50 to 1110, wherein the excipient granules have a re-adjusted viscosity characterized by a viscosity of 15 cP to 35 cP within 5 seconds and 40 cP to 60 cP within 60 seconds.

[0507] Embodiment 112. The pharmaceutical composition according to any one of Embodiments 50 to 111, wherein the excipient granules have a re-adjusted viscosity as shown in Figure 5.

[0508] Embodiment 113. The pharmaceutical composition according to any one of Embodiments 50 to 112, wherein the excipient granules have a re-adjusted brightness characterized by a brightness of 70 to 75 within 30 seconds.

[0509] Embodiment 114. The pharmaceutical composition according to any one of Embodiments 50 to 113, wherein the excipient granules have a re-adjusted viscosity as shown in Figure 6.

[0510] Embodiment 115. The pharmaceutical composition according to any one of Embodiments 1 to 114, wherein the excipient granules have a first bulk density, and the pharmaceutical granules have a second bulk density, and the first bulk density is within + / - 20% of the second bulk density.

[0511] Embodiment 116. The pharmaceutical composition according to any one of Embodiments 1 to 115, wherein the excipient granules have a first average particle size, the pharmaceutical granules have a second average particle size, and the first average particle size is within + / - 20% of the second average particle size.

[0512] Embodiment 117. The pharmaceutical composition according to any one of Embodiments 1 to 116, wherein the excipient granules have a first tap density, the pharmaceutical granules have a second tap, and the first average tap density is within + / - 20% of the tap density.

[0513] Embodiment 118. The pharmaceutical composition according to any one of Embodiments 1 to 117, wherein the excipient granules have a first Hausner ratio, and the pharmaceutical granules have a second Hausner ratio, and the first Hausner ratio is within + / - 20% of the second Hausner ratio.

[0514] Embodiment 119. The pharmaceutical composition according to any one of Embodiments 1 to 118, wherein the excipient granules have a first compressibility index, the pharmaceutical granules have a second compressibility index, and the first compressibility index is within + / - 20% of the second compressibility index.

[0515] Embodiment 120. The pharmaceutical composition according to any one of Embodiments 1 to 119, wherein the excipient granules have a first Flodex value, the pharmaceutical granules have a second Flodex value, and the first Flodex value is within + / - 20% of the second Flodex value.

[0516] Embodiment 121. The pharmaceutical composition according to any one of Embodiments 1 to 120, wherein the excipient granules have a first abrasion value, the pharmaceutical granules have a second abrasion value, and the first abrasion value is within + / - 20% of the second abrasion value.

[0517] Embodiment 122. The pharmaceutical composition according to Embodiments 1 to 121, wherein the pharmaceutical composition comprises one or more additional excipients.

[0518] Embodiment 123. The pharmaceutical composition according to Embodiment 122, wherein the one or more additional excipients are in the form of a powder.

[0519] Embodiment 124. The pharmaceutical composition according to any one of Embodiments 122 to 123, wherein the pharmaceutical composition comprises one or more additional excipients in less than 5% by weight, and the weight percentage is based on the total weight of the pharmaceutical composition.

[0520] Embodiment 125. The pharmaceutical composition according to any one of Embodiments 122 to 124, wherein the one or more additional excipients include an antistatic agent.

[0521] Embodiment 126. The pharmaceutical composition according to Embodiment 125, wherein the antistatic agent comprises a hydrated magnesium silicate.

[0522] Embodiment 127. The pharmaceutical composition according to any one of Embodiments 125 to 126, wherein the pharmaceutical composition contains 0.1% to 1.0% by weight of the antistatic agent, and the weight percentage is based on the total weight of the pharmaceutical composition.

[0523] Embodiment 128. A pharmaceutical product comprising the pharmaceutical composition described in any one of Embodiments 1 to 127.

[0524] Embodiment 129. The pharmaceutical product according to Embodiment 128, wherein the pharmaceutical product comprises the pharmaceutical composition contained within a package.

[0525] Embodiment 130. The pharmaceutical product according to Embodiment 129, wherein the package includes a sachet.

[0526] Embodiment 131. The pharmaceutical product according to any one of Embodiments 129 to 130, wherein the pharmaceutical product includes the excipient granules and pharmaceutical granules combined in the same package.

[0527] Embodiment 132. The pharmaceutical product according to any one of Embodiments 129 to 121, wherein the pharmaceutical product comprises a first package containing the excipient granules and a second package containing the pharmaceutical granules.

[0528] Embodiment 133. The product according to Embodiment 132, wherein the first package and the second package include a sachet.

[0529] Embodiment 134. The pharmaceutical product according to Embodiment 128, wherein the pharmaceutical product comprises a first package containing the excipient granules, a second package containing the immediate-release pharmaceutical granules, and a third package containing the adjusted-release pharmaceutical granules.

[0530] Embodiment 135. The pharmaceutical product according to Embodiment 134, wherein each of the first package, the second package, and the third package is a sachet or a stick pack.

[0531] Embodiment 136. The pharmaceutical product according to Embodiment 128, wherein the pharmaceutical product includes a first compartment for containing the excipient granules and a second compartment for containing the pharmaceutical granules.

[0532] Embodiment 137. The pharmaceutical product according to Embodiment 128, wherein the pharmaceutical product includes a first compartment for containing the excipient granules, a second compartment for containing the immediate-release pharmaceutical granules, and a third compartment for containing the adjusted-release pharmaceutical granules.

[0533] Embodiment 138. The pharmaceutical product according to any one of Embodiments 128 to 137, wherein the pharmaceutical product is configured to provide a pharmaceutical composition containing the excipient granules and the pharmaceutical granules by combining the excipient granules with the pharmaceutical granules during use.

[0534] Embodiment 139. The pharmaceutical product according to any one of Embodiments 128 to 138, wherein the pharmaceutical product comprises 0.5 g to 25 g of the pharmaceutical composition.

[0535] Embodiment 140. The pharmaceutical product according to any one of Embodiments 128 to 139, wherein the pharmaceutical product contains a therapeutically effective dose of 4-((L-valyl)oxy)butanoic acid.

[0536] Embodiment 141. The product according to any one of Embodiments 128 to 140, wherein the pharmaceutical product contains 2 g to 20 g of 4-((L-valyl)oxy)butanoic acid.

[0537] Embodiment 142. A unit dose comprising the pharmaceutical composition described in any one of Embodiments 1 to 127.

[0538] Embodiment 143. The unit dose according to Embodiment 142, wherein the unit dose contains 2 g to 20 g of 4-((L-valyl)oxy)butanoic acid.

[0539] Appearance 144. A partial unit dose comprising the pharmaceutical composition described in any one of Appearances 1 to 127.

[0540] Embodiment 145. The partial unit dose according to Embodiment 144, wherein the partial unit dose contains 2 g to 20 g of 4-((L-valyl)oxy)butanoic acid.

[0541] Embodiment 146. A kit comprising a pharmaceutical composition described in any one embodiment of Embodiments 1 to 127, a pharmaceutical product described in any one embodiment of Embodiments 128 to 141, and instructions for using the contents of the kit.

[0542] Embodiment 147. A method for preparing an oral pharmaceutical composition for oral administration using a pharmaceutical composition described in any one embodiment of Embodiments 1 to 127 or a pharmaceutical product described in any one embodiment of Embodiments 128 to 141, comprising: combining the pharmaceutical composition with an aqueous solution; and mixing the pharmaceutical composition to dissolve immediate-release pharmaceutical granules and excipient granules to form a viscous oral pharmaceutical composition.

[0543] Embodiment 148. The method according to Embodiment 147, wherein the aqueous solution is water.

[0544] Embodiment 149. The method according to Embodiment 417, wherein the aqueous solution is tap water at a temperature of 20°C to 25°C.

[0545] Embodiment 150. The method according to any one of Embodiments 147 to 149, wherein the viscous oral pharmaceutical composition has a viscosity of 50 cP to 1,000 cP at a temperature of 23°C, and the viscosity is determined using a Brookfield digital viscometer model LVDV-I+ equipped with a Brookfield SC4-18 spindle at a spindle speed of 30 rpm.

[0546] Embodiment 151. The method according to any one of Embodiments 147 to 150, wherein the method comprises combining the pharmaceutical composition and the aqueous solution in a weight-to-volume ratio of 0.25 to 0.74, wherein the ratio is obtained by dividing the weight of the pharmaceutical composition in grams by the volume of the aqueous solution in milliliters.

[0547] Embodiment 152. The method according to any one of Embodiments 147 to 151, wherein the method comprises adjusting the aqueous solution to the pharmaceutical composition in a volume / weight ratio of 1.5 to 2.5, and the ratio refers to the result of dividing the volume of the aqueous solution in mL units by the weight of the pharmaceutical composition in grams units.

[0548] Embodiment 153. The method according to any one of Embodiments 147 to 152, wherein the adjusted release pharmaceutical granules are suspended in the viscous solution.

[0549] Embodiment 154. An oral pharmaceutical composition prepared by mixing the pharmaceutical composition described in any one of Embodiments 1 to 127 with water.

[0550] Embodiment 155. An oral pharmaceutical composition according to Embodiment 154, comprising combining 10 g to 25 g of the pharmaceutical composition with 30 mL to 50 mL of water.

[0551] Embodiment 156. The oral pharmaceutical composition according to any one of Embodiments 154 to 155, wherein the oral pharmaceutical composition comprises a viscous aqueous solution and adjusted release granules suspended in the viscous aqueous solution.

[0552] Embodiment 157. The oral pharmaceutical composition according to Embodiment 156, wherein the viscous aqueous solution has a viscosity of 50 cP to 1,000 cP at a temperature of 20°C to 25°C, such as 23°C, and the viscosity is determined by adding 3,164 mg of the pharmaceutical composition to 40 mL of water and mixing them together, and using a Brookfield digital viscometer model LVDV-I+ equipped with a Brookfield SC4-18 spindle at a spindle speed of 30 rpm.

[0553] Embodiment 158. The oral pharmaceutical composition according to any one of Embodiments 156 to 157, wherein the viscous solution contains dissolved 4-((L-valyl)oxy)butanoic acid.

[0554] Embodiment 159. The oral pharmaceutical composition according to any one of Embodiments 154 to 158, wherein the oral pharmaceutical composition has a volume of 30 mL to 60 mL.

[0555] Embodiment 160. The oral pharmaceutical composition according to Embodiment 154, wherein the oral pharmaceutical composition comprises a viscous solution containing dissolved 4-((L-valyl)oxy)butanoic acid and an adjusted release granule containing 4-((L-valyl)oxy)butanoic acid suspended in the viscous solution.

[0556] Embodiment 161. The oral pharmaceutical composition according to Embodiment 160, wherein 17% to 37% by weight of the 4-((L-valyl)oxy)butanoic acid is dissolved in the viscous solution, and the adjusted-release pharmaceutical granules contain 63% to 83% by weight of the 4-((L-valyl)oxy)butanoic acid, and the weight percentage is based on the total weight of the 4-((L-valyl)oxy)butanoic acid in the oral pharmaceutical composition.

[0557] Embodiment 162. The oral pharmaceutical composition according to any one of Embodiments 154 to 160, wherein the oral pharmaceutical composition contains a therapeutically effective dose of 4-((L-valyl)oxy)butanoic acid.

[0558] Embodiment 163. The oral pharmaceutical composition according to any one of Embodiments 154 to 161, wherein the oral pharmaceutical composition contains a unit dose of 4-((L-valyl)oxy)butanoic acid.

[0559] Embodiment 164. An oral pharmaceutical composition according to any one of Embodiments 156 to 163, wherein the viscous solution has a volume of about 40 mL.

[0560] Embodiment 165. An oral pharmaceutical composition according to any one of Embodiments 156 to 163, wherein the viscous solution has a volume of 20 mL to 60 mL.

[0561] Embodiment 166. An oral pharmaceutical composition according to any one of Embodiments 156 to 165, wherein the viscous oral solution contains 10 g to 20 g of 4-((L-valyl)oxy)butanoic acid.

[0562] Embodiment 167. A method for treating a disease in a patient, comprising orally administering a therapeutically effective amount of an oral pharmaceutical composition according to any one of Embodiments 154 to 166 to a patient in need of such treatment.

[0563] Embodiment 168. The method according to Embodiment 167, wherein the disease can be treated with γ-hydroxybutyrate.

[0564] Embodiment 169. The method according to Embodiment 167, wherein the disease is selected from narcolepsy, cataplexy, cataplexy with narcolepsy, excessive daytime sleepiness, sleep disorders associated with Parkinson's disease, Parkinson's disease, neurodegenerative diseases, sleep disorder syndromes, fatigue, improvement of nocturnal sleep, hypnagogic hallucinations, sleep paralysis, fragmented sleep, alcohol withdrawal / dependence, obstructive sleep apnea syndrome, insomnia, insomnia associated with schizophrenia, difficulty falling asleep and maintaining sleep, chronic fatigue syndrome, essential tremor, hemiplegia in children with alternating hemiplegia, sedative abuse, and binge eating disorder.

[0565] Embodiment 170. The method according to Embodiment 167, wherein the disorder is excessive daytime sleepiness associated with fatigue or narcolepsy.

[0566] Embodiment 171. The method according to Embodiment 167, wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy associated with narcolepsy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia.

[0567] Embodiment 172. The method according to Embodiment 167, wherein the disease is a cataplexy-related seizure.

[0568] Embodiment 173. The method according to Embodiment 167, wherein the disorder is excessive daytime sleepiness associated with narcolepsy.

[0569] Embodiment 174. The method according to Embodiment 167, wherein the disease is excessive daytime sleepiness in patients with Parkinson's disease.

[0570] Embodiment 175. The method according to Embodiment 167, wherein the disease is chronic fatigue in a patient with Parkinson's disease.

[0571] Apparatus 176. A method for treating symptoms associated with narcolepsy, excessive daytime sleepiness, cataplexy, excessive daytime sleepiness associated with narcolepsy, excessive daytime sleepiness associated with Parkinson's disease, excessive daytime sleepiness associated with multiple sclerosis, cataplexy, fatigue, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, or fibromyalgia, comprising orally administering a therapeutically effective amount of an oral pharmaceutical composition according to any one of Apparatus 154 to 166 to a patient in need of such treatment.

[0572] Apparatus 177. A method for treating REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety disorder, comprising orally administering a therapeutically effective amount of an oral pharmaceutical composition according to any one of Apparatus 154 to 166 to a patient in need of such treatment.

[0573] Apparatus 178. A method for treating symptoms associated with REM sleep behavior disorder, spasmodic dystonia, schizophrenia, insomnia, insomnia associated with schizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, cluster headache, Alzheimer's disease, essential tremor, post-traumatic stress syndrome, insomnia associated with post-traumatic stress syndrome, or anxiety disorder, comprising orally administering a therapeutically effective amount of an oral pharmaceutical composition according to any one of Apparatus 154 to 166 to a patient in need of such treatment.

[0574] Embodiment 179. The method according to any one of Embodiments 167 to 178, wherein administration includes administration by QD.

[0575] Embodiment 180. The method according to any one of Embodiments 167 to 178, wherein administration includes administration by BID.

[0576] Embodiment 181. A pharmaceutical composition according to any one of Embodiments 1 to 127, wherein, after being stored in a sealed high-barrier pouch at 5±3°C or 25±2°C / 60±5%RH for 18 months, the 4-((L-valyl)oxy)butanoic acid solubility profile is the same as the 4-((L-valyl)oxy)butanoic acid solubility profile before storage.

[0577] Apparatus 182. The pharmaceutical composition provided by this disclosure is sealed in a high-barrier pouch and stored at 5±3°C or 25±2°C / 60±5%RH for 18 months, after which the re-preparation time is approximately 15 seconds. The pharmaceutical composition according to Apparatus 1 to 127.

[0578] Embodiment 183. A pharmaceutical composition according to any one of Embodiments 1 to 127, wherein, after being stored in a sealed high-barrier pouch at 5±3°C or 25±2°C / 60±5%RH for 18 months, the soluble content of 4-((L-valyl)oxy)butanoic acid is greater than 96% of the soluble profile of 4-((L-valyl)oxy)butanoic acid before storage.

[0579] Embodiment 184. A pharmaceutical composition according to any one of Embodiments 1 to 127, wherein the total impurity content is 0.3% or less after being stored at 5±3℃ for 18 months in a sealed high-barrier pouch, and the total impurity content is 0.6% or less after being stored at 25±2℃ / 60±5%RH in a sealed high-barrier pouch for 18 months.

[0580] Embodiment 185. The pharmaceutical composition according to any one of claims 1 to 127, wherein the L-valine impurity content is 0.3% or less after storage in a sealed high-barrier pouch at 5±3°C for 18 months, and the L-valine impurity content is 0.4% or less after storage in a sealed high-barrier pouch at 25±2°C / 60±5%RH or therein for 18 months. [Examples]

[0581] The embodiments provided herein are further illustrated by reference to the following examples describing pharmaceutical granules, excipient granules, and pharmaceutical compositions. It will be apparent to those skilled in the art that many modifications to both materials and methods can be made without departing from the scope of this disclosure. It should be noted that alternative methods exist for carrying out the embodiments disclosed herein. Therefore, these embodiments should be considered illustrative and not limiting. Furthermore, the claims are not limited to the details given herein, and the full scope and their equivalents are reserved.

[0582] General method Plasma concentrations of 4-((L-valyl)oxy)butanoic acid and γ-hydroxybutyrate in healthy human plasma were measured using liquid chromatography-tandem mass spectrometry and evaluated using PHOENIX® WINNONLIN® version 8.1 (Pharsight Corporation, USA) and MICROSOFT® EXCEL® 2016 (Microsoft Corporation, USA).

[0583] Example 1 Immediate-release pharmaceutical granules Immediate-release drugs having the components listed in Table 1 were prepared.

[0584] Immediate-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid were prepared using MicroPX® micropelletization technology (Glatt GmbH). The immediate-release pharmaceutical granules had an average granule size (D50) of 225 μm to 275 μm. The immediate-release pharmaceutical granules contained 90 wt% 4-((L-valyl)oxy)butanoic acid, 5 wt% USP magnesium silicate, and 5 wt% hypromellose (hydroxypropyl methylcellulose), where wt% is based on the total weight of the immediate-release pharmaceutical granules. [Table 1]

[0585] Immediate-release granules were prepared using a continuous fluidized bed pelletizing process involving a combination of layering, coating, and partial spray drying.

[0586] The yield in the target particle size range of 200 μm to 500 μm was over 90%.

[0587] The dissolution profile for immediate-release pharmaceutical granules was determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 75 rpm. The dissolution profile for the release of 4-((L-valyl)oxy)butanoic acid from the immediate-release pharmaceutical granules is shown in Figure 1.

[0588] Example 2 Modified release pharmaceutical granules Adjusted-release pharmaceutical granules having the components listed in Table 2 were prepared. [Table 2]

[0589] The controlled-release granules were prepared using a Wurster fluidized bed coating. The immediate-release granules of Example 1 were coated in a fluidized bed equipped with a Wurster column. The coating contained 73.0% by weight ethylcellulose, 4.1% by weight hydroxypropylcellulose, 7.4% by weight dibutyl sebacate, and 15.6% by weight talc, where the percentages are based on the total weight of the coating. See Table 2. Since the coating did not contain a pH-dependent release polymer, the release profile of the controlled-release pharmaceutical granules was not affected by food, gastric emptying time, or gastric pH. After coating, a weight increase of 20% wg was obtained.

[0590] The dissolution profile for the controlled-release pharmaceutical granules was determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 75 rpm. The dissolution profile for the release of 4-((L-valyl)oxy)butanoic acid from the controlled-release pharmaceutical granules is shown in Figure 2.

[0591] The dissolution profile was measured using an autosampler equipped with an Agilent dissolution bath and an Apparatus II paddle. The dissolution solvent was prepared by mixing 2.99 g of sodium acetate trihydrate, 1.2 mL of glacial acetic acid, and 1,000 mL of water, and the pH was adjusted to 4.5 ± 0.05 using acetic acid. 500 mL of the dissolution solvent was transferred to a container and the temperature was equilibrated to 37 °C ± 0.5 °C. Pharmaceutical granules (3,164 mg), including immediate-release and controlled-release granules, were added while rotating the paddle at 75 rpm. Samples were taken at intervals, and the content of 4-((L-valyl)oxy)butanoic acid was measured using HPLC.

[0592] Dissolution profiles for pharmaceutical granules containing immediate-release (Example 1) and controlled-release granules were determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 75 rpm. The pharmaceutical granules contained approximately 73 wt% controlled-release granules and approximately 27 wt% immediate-release granules. The dissolution profile for the release of 4-((L-valyl)oxy)butanoic acid from the pharmaceutical granules is shown in Figure 3.

[0593] Example 3 Excipient granules Excipient granules having the components listed in Table 3 were prepared. [Table 3]

[0594] Excipient granules were prepared using high-shear granules. pharmaceutically acceptable excipients were selected to optimize the administration and taste of the 4-((L-valyl)oxy)butanoic acid-containing oral pharmaceutical composition.

[0595] Methods for producing excipient granules included (1) dry granulation through roller compression and / or slug tableting on a tablet press, and (2) high-shear wet granulation using either a small coffee grinder for small-scale experiments or a 4L bowl high-shear granulator for larger batch sizes.

[0596] Excipient granules were prepared by drying and mixing the constituent components, then granulating the dried mixture with a buffer containing sodium citrate dihydrate and anhydrous citrate dissolved in water to provide a first granule. The first granule was wet-molded to provide a first wet mass, and then granulated with water to provide a second granule. The second granule was wet-molded to provide a second wet mass, and then dried to provide excipient granules.

[0597] For granulation, a Collette (GEA) GRAL 25 high-shear granulator equipped with a 25L jacked bowl was used. The jacketed bowl was coupled to an Advantage Engineering air-cooled water cooler set to 46°F (8°C). Buffer or water was sprayed onto the mixture at an atomization pressure of 45 bar using a two-fluid nozzle with a 1-mm nozzle orifice.

[0598] The excipient granules were dried at 60°C using a Freund-Vector FLM-3 fluidized bed dryer.

[0599] The dried excipient granules were ground using a Quadro Comil® 197 equipped with a 50G or 32G screen and sieved using a benchtop vibrating sieve base equipped with #35 and #70 mesh screens. Fine particles (<210 μm) passing through the #70 mesh screen were removed.

[0600] Figure 4 shows the particle size distribution of excipient granules prepared at different stages of the sieving process. The size distribution includes the distribution of bulk granules before sieving (bulk), in the 35G–75G screen fraction (35–70), after passing through the 50G screen (50G), and after passing through the 32G screen (30G). The particle size distribution was determined using sieve analysis or laser diffraction.

[0601] A viscous solution was prepared by mixing 1.2 g of excipient granules with 40 mL of water. The pH of the prepared viscous solution was 4.3.

[0602] The re-adjusted viscosity profile for the excipient granules is shown in Figure 5. The re-adjusted viscosity was determined using a Brookfield digital viscometer model LVDV-I+ equipped with a Brookfield SC4-18 spindle at a speed of 30 rpm. Excipient granules (1.2 g) were added to 40 mL of water at 23 °C.

[0603] The reprocessing brightness profile for the excipient granules is shown in Figure 6 for the same solution used to measure the reprocessing viscosity.

[0604] The excipient granules had a bulk density of 0.58 g / mL to 0.62 g / mL, a tap density of 0.69 g / mL to 0.74 g / mL, a Hausner ratio of 0.18 to 1.20, a compressibility index of 15.5 to 16.8, and a Flodex value of 4.

[0605] Example 4 Oral pharmaceutical composition An oral pharmaceutical composition was prepared by combining the immediate granules of Example 1, the controlled-release pharmaceutical granules of Example 2, and the excipient granules of Example 3.

[0606] Table 4 shows the relative amounts of immediate-release granules and adjusted-release granules in %w / w of the pharmaceutical granules, the amount of 4-((L-valyl)oxy)butanoic acid in the immediate-release and adjusted-release granules, respectively, and the %w / w of 4-((L-valyl)oxy)butanoic acid in the immediate-release and adjusted-release granules based on the total weight of 4-((L-valyl)oxy)butanoic acid in the pharmaceutical composition. [Table 4]

[0607] Table 5 shows the amounts of components in an oral pharmaceutical composition containing 14.5 g of 4-((L-valyl)oxy)butanoic acid. The dose refers to the dose of 4-((L-valyl)oxy)butanoic acid. [Table 5]

[0608] The dissolution profiles for pharmaceutical compositions containing excipients, immediate-release granules, and controlled-release granules were determined using a USP Type 2 dissolution apparatus with a pH 4.5 buffer solution at a temperature of 37°C and a paddle speed of 75 rpm. The pharmaceutical compositions contained approximately 67 wt% controlled-release granules, approximately 25.2 wt% immediate-release pharmaceutical granules, and approximately 7.6 wt% excipient granules. Sodium acetate buffer solution was used as the dissolution solvent, with 3,164 mg of the pharmaceutical composition in 500 mL of the dissolution solvent. The dissolution profiles are shown in Figure 7.

[0609] The viscosity of the re-prepared pharmaceutical composition was adjusted by mixing 14.5 g of the stored pharmaceutical composition with 40 mL of water at 23°C and using a No. 62 spindle at a speed of 12 rpm. <912> The viscosity was determined by measuring it according to Method 1c. The results are shown in Figure 8.

[0610] Example 5 Pharmacokinetics of pharmaceutical granules The immediate-release pharmaceutical granules of Example 1 and the adjusted-release pharmaceutical granules of Example 2 were combined and administered orally with water to 12 fasted, healthy subjects. To prepare the combined oral pharmaceutical composition, the immediate-release pharmaceutical granules were dissolved in 30 mL of water. The adjusted-release pharmaceutical granules were then added and gently mixed by vortexing. 30 mL of the oral suspension vehicle, Ora-Plus®, was added, and the suspension was gently stirred. The subjects then drank this suspension. The subjects repeatedly rinsed the cup with up to 250 mL of water and drank the solution.

[0611] Table 6 provides a description of the oral medications administered. [Table 6]

[0612] Table 7 provides specific plasma γ-hydroxybutyrate pharmacokinetic parameters, and Figure 9 shows the corresponding plasma γ-hydroxybutyrate pharmacokinetic profiles. [Table 7]

[0613] Example 6 Storage stability The storage stability of combined immediate-release pharmaceutical granules and controlled-release pharmaceutical granules, as well as separately, pharmaceutical compositions containing excipient granules and pharmaceutical granules, was determined.

[0614] Pharmaceutical granules were prepared by combining the immediate-release (IR) granules of Example 1 (approximately 27% by weight) and the controlled-release (MR) granules of Example 2 (approximately 73% by weight), with the weight percentages being based on the total weight of the pharmaceutical granules. A sample (3.61 g) of the combination of immediate-release pharmaceutical granules (Example 1) and controlled-release pharmaceutical granules (Example 2) was prepared and placed in a high-barrier pouch (Amcor RFA-045, specification number 91038).

[0615] The pouches containing the pharmaceutical compositions were stored under accelerated conditions for up to 24 months at (1) refrigeration at 5±3°C, (2) storage at 25±2°C / 60±5%RH, or (3) storage at 40±2°C / 75±5%RH. The 4-((L-valyl)oxy)butanoic acid content after storage is shown in Table 8. [Table 8]

[0616] Table 9 shows the amounts of L-valine impurities and total impurities in the sample. [Table 9]

[0617] Table 10 shows the amount of water in the sample. [Table 10]

[0618] The dissolution profiles of the pharmaceutical granule samples stored under conditions (1) and (2) are shown in Figures 10A and 10B, respectively. The profiles represent storage for 0, 3, 6, 9, 12, and 18 months under the test conditions. The dissolution profiles were determined as described in Example 2. The dissolution solvent contained 3,164 mg of pharmaceutical granules in 500 mL of water.

[0619] Similar stability tests were performed on pharmaceutical compositions containing excipient granules (EG), immediate-release pharmaceutical granules (IR), and controlled-release granules (MR). The granules were combined, and 4 grams of the pharmaceutical composition was placed in a high-barrier pouch (Amcor RFA-045, specification number 91038). The samples were stored for up to 24 months under test conditions (1) to (3). The samples contained approximately 7.6% by weight of the excipient granules of Example 3, approximately 25.2% by weight of the immediate-release pharmaceutical granules of Example 1, and approximately 67.2% by weight of the controlled-release pharmaceutical granules of Example 2.

[0620] Table 11 shows the 4-((L-valyl)oxy)butanoic acid content after storage, Table 12 shows the impurity content, Table 13 shows the water content, and Table 14 shows the re-preparation time. The 4-((L-valyl)oxy)butanoic acid and impurity content were determined using HPLC, and the water content was determined using USP. <921> The preparation time was determined according to Method 1c and visually evaluated. [Table 11] [Table 12] [Table 13] [Table 14]

[0621] The dissolution profiles for the pharmaceutical compositions stored under conditions (1) and (2) are shown in Figures 11A and 11B, respectively. The profiles represent storage for 0, 3, 6, 9, 12, and 18 months under the test conditions. The dissolution profiles were measured using an autosampler equipped with an Agilent dissolution bath and an Apparatus II paddle. The dissolution solvent was prepared by mixing 2.99 g of sodium acetate trihydrate, 1.2 mL of glacial acetic acid, and 1,000 mL of water, and the pH was adjusted to 4.5 ± 0.05 using acetic acid. 500 mL of the dissolution solvent was transferred to a container and the temperature was equilibrated to 37 °C ± 0.5 °C. The pharmaceutical composition (3,164 mg) was added while rotating the paddle at 75 rpm. Samples were taken at intervals, and the content of 4-((L-valyl)oxy)butanoic acid was measured using HPLC.

[0622] It should be noted that alternative methods exist for carrying out the embodiments disclosed herein. Therefore, these embodiments should be considered illustrative and not restrictive. Furthermore, the claims are not limited to the details given herein, and the full scope of those claims and their equivalents are reserved.

Claims

1. A pharmaceutical composition, A pharmaceutical granule containing 4-((L-valyl)oxy)butanoic acid, A pharmaceutical composition comprising excipient granules.

2. The pharmaceutical composition comprises 2% to 12% by weight of the excipient granules, The pharmaceutical composition according to claim 1, wherein the weight percentage is based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition comprises 86% to 98% by weight of the pharmaceutical granules, The pharmaceutical composition according to claim 1, wherein the weight percentage is based on the total weight of the pharmaceutical composition.

4. The aforementioned pharmaceutical granules An immediate-release pharmaceutical granule containing multiple immediate-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid, The pharmaceutical composition according to claim 1, comprising a modified-release pharmaceutical granule containing a plurality of modified-release pharmaceutical granules containing 4-((L-valyl)oxy)butanoic acid.

5. The excipient granules comprising multiple excipient granules, and The excipient granules are Viscosity-reducing agent, Disintegrant, The pharmaceutical composition according to claim 1, comprising one or more additional excipients.

6. The aforementioned excipient granules A binder in an amount of 2% to 22% by weight, Diluent in an amount of 10% to 30% by weight, 1% to 20% by weight of filler, Flavoring agents in an amount of 15% to 35% by weight, 0.5% to 6.5% by weight of cushioning material, 0.5% to 8% by weight of acid, and / or Contains 0.1% to 6% by weight of sweeteners, The pharmaceutical composition according to claim 5, wherein the weight percentage is based on the total weight of the excipient granules.

7. The aforementioned excipient granules The viscosity-reducing agent in an amount of 1% to 35% by weight, The disintegrant is present in an amount of 1% to 25% by weight, The pharmaceutical composition according to claim 5, wherein the weight percentage is based on the total weight of the excipient granules.

8. The pharmaceutical composition according to claim 5, wherein, after being sealed in a high-barrier pouch and stored at 5±3°C or 25±2°C / 60±5% RH for 18 months, the 4-((L-valyl)oxy)butanoic acid solubility profile is the same as the 4-((L-valyl)oxy)butanoic acid solubility profile before storage. The pharmaceutical composition provided by this disclosure is sealed in a high-barrier pouch and stored at 5±3°C or 25±2°C / 60±5% RH for 24 months, after which the re-preparation time is approximately 15 seconds.

9. The pharmaceutical composition according to claim 5, wherein, after being sealed in a high-barrier pouch and stored at 5±3°C or 25±2°C / 60±5% RH for 18 months, the 4-((L-valyl)oxy)butanoic acid content exceeds 96% of the 4-((L-valyl)oxy)butanoic acid content before storage.

10. The pharmaceutical composition according to claim 5, wherein, after being sealed in a high-barrier pouch and stored at 5±3°C for 18 months, the total impurity content is 0.3% or less, and after being sealed in a high-barrier pouch and stored at 25±2°C / 60±5% RH, or therein, for 18 months, the total impurity content is 0.6% or less.

11. The pharmaceutical composition according to claim 5, wherein the L-valine impurity content is 0.3% or less after being stored in a sealed high-barrier pouch at 5±3°C for 18 months, and the L-valine impurity content is 0.4% or less after being sealed in a high-barrier pouch and stored at 25±2°C / 60±5% RH or therein for 18 months.

12. A pharmaceutical product comprising the pharmaceutical composition described in claim 1.

13. It's a kit, The pharmaceutical composition according to claim 1, A kit including instructions for using the contents of the kit.

14. An oral pharmaceutical composition prepared by mixing the pharmaceutical composition described in claim 1 with water.

15. The oral pharmaceutical composition A viscous aqueous solution and The oral pharmaceutical composition according to claim 14, comprising a controlled release granule suspended in the viscous aqueous solution.

16. The oral pharmaceutical composition according to claim 14, wherein the viscous aqueous solution has a viscosity of 50 cP to 1,000 cP at a temperature of 23°C, and the viscosity is determined according to USP<912> Method 1c at a concentration of 0.30 to 0.42 g / mL using a 12 rpm No. 62 spindle.

17. A method for treating a disease in a patient, comprising orally administering a therapeutically effective amount of the oral pharmaceutical composition according to claim 14 to a patient in need of such treatment.

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